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ZHAO K, GUO C, CHEN Y, LI S. [Advances in the Application of Adjuvant Chemotherapy and Targeted Therapy
in Postoperative Patients with Stage I Lung Adenocarcinoma]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2024; 27:777-784. [PMID: 39631834 PMCID: PMC11629094 DOI: 10.3779/j.issn.1009-3419.2024.101.26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Indexed: 12/07/2024]
Abstract
Lung cancer is one of the main causes of cancer burden and death in China, with nearly 800,000 newly diagnosed lung cancer patients each year, nearly half of whom are lung adenocarcinoma (LUAD) patients. According to current clinical guidelines, surgery is the main treatment for stage I LUAD patients, but the 5-year overall survival rate of stage I LUAD patients alone is still unsatisfactory, about 73%-90%, indicating that a considerable number of patients require other means to improve survival benefits. Chemotherapy and targeted therapy have achieved great success in the treatment of locally advanced and metastatic LUAD patients, but there is still controversy over whether they can benefit stage I LUAD postoperative patients. Under the circumstances, many researchers have paid attention to this issue and made beneficial explorations. This review provides a brief review of the factors that affect the acceptance of adjuvant chemotherapy and targeted therapy in stage I LUAD postoperative patients, as well as the relevant clinical research on the application of adjuvant chemotherapy and targeted therapy in stage I LUAD postoperative patients, in order to gain a broader understanding of the latest developments in this field and find new breakthroughs to promote sustained research in this field.
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Li L, Li S, Zhang X, Mei L, Fu X, Dai M, Wei N. Establishing the role of BRCA1 in the diagnosis, prognosis and immune infiltrates of breast invasive cancer by bioinformatics analysis and experimental validation. Aging (Albany NY) 2024; 16:1077-1095. [PMID: 38224491 PMCID: PMC10866431 DOI: 10.18632/aging.205366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/16/2023] [Indexed: 01/17/2024]
Abstract
BACKGROUND Breast cancer susceptibility gene 1 (BRCA1) is a well-known gene that acts a vital role in suppressing the growth of tumors. Previous studies have primarily focused on the genetic mutations of BRCA1 and its association with hereditary breast invasive carcinoma (BRCA). However, little research has been done to investigate the relationship between BRCA1 and immune infiltrates and prognosis in BRCA. METHODS We obtained the expression profiles and clinical information of patients with BRCA from the Cancer Genome Atlas (TCGA) database. The levels of the BRCA1 gene between BRCA tissues and normal breast tissues were compared through the Wilcoxon rank-sum test. Additionally, we performed WB and RT-qPCR techniques to detect the expression of BRCA1. We conducted functional enrichment analyses. Furthermore, we assessed immune cell infiltration using a single-sample gene set enrichment analysis. The methylation status of the BRCA1 gene was analyzed using the UALCAN and MethSurv databases. The Cox regression analysis and (KM) Kaplan-Meier method were employed to determine the prognostic value of BRCA1. In order to provide a practical tool for predicting the overall survival rates at different time points, we also constructed a nomogram. RESULTS Our analysis revealed that the expression of BRCA1 was significantly higher in BRCA tissues compared to normal tissues. Furthermore, this increased level of BRCA1 was found to be associated with specific BRCA subtypes, including T2, stage II, ER positive, ect. Importantly, the overexpression of BRCA1 was shown to be a negative prognostic marker for the overall survival rates of BRCA patients. Moreover, low methylation status of the BRCA1 gene was related to a poorer prognosis. Furthermore, our results indicated that high levels of BRCA1 are related to a decrease in level of killer immune cells, such as natural killer (NK) cells, macrophages, CD8+ T cells, and plasma-like dendritic cells (pDCs) within the tumor microenvironment. CONCLUSIONS Our study is the first to provide evidence indicating that the presence of BRCA1 can serve as a reliable marker for both diagnosing and determining the prognosis of BRCA. Moreover, BRCA1 acts as a crucial indicator of the cancer's potential to infiltrate and invade the immune system, which has important implications for developing targeted therapies in BRCA.
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Affiliation(s)
- Leilei Li
- Department of Pathology, Kunming Medical University, Kunming 650500, Yunnan, China
| | - Shuangyan Li
- Department of Oncology, Kunming Medical University, Kunming 650500, Yunnan, China
| | - Xuyang Zhang
- Department of Hepatobiliary, Second Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou, China
| | - Liying Mei
- Department of Breast Surgery, Guizhou Provincial People’s Hospital, Guiyang 550002, Guizhou, China
| | - Xueqin Fu
- Department of Breast Surgery, Guizhou Provincial People’s Hospital, Guiyang 550002, Guizhou, China
| | - Min Dai
- Department of Breast Surgery, Guizhou Provincial People’s Hospital, Guiyang 550002, Guizhou, China
| | - Na Wei
- Department of Breast Surgery, Guizhou Provincial People’s Hospital, Guiyang 550002, Guizhou, China
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Mao L, Wu J, Zhang Z, Mao L, Dong Y, He Z, Wang H, Chi K, Jiang Y, Lin D. Prognostic Value of Chromatin Structure Typing in Early-Stage Non-Small Cell Lung Cancer. Cancers (Basel) 2023; 15:3171. [PMID: 37370781 DOI: 10.3390/cancers15123171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/08/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
(1) Background: Chromatin structure typing has been used for prognostic risk stratification among cancer survivors. This study aimed to ascertain the prognostic values of ploidy, nucleotyping, and tumor-stroma ratio (TSR) in predicting disease progression for patients with early-stage non-small cell lung cancer (NSCLC), and to explore whether patients with different nucleotyping profiles can benefit from adjuvant chemotherapy. (2) Methods: DNA ploidy, nucleotyping, and TSR were measured by chromatin structure typing analysis (Matrix Analyser, Room4, Kent, UK). Cox proportional hazard regression models were used to assess the relationships of DNA ploidy, nucleotyping, and TSR with a 5-year disease-free survival (DFS). (3) Results: among 154 early-stage NSCLC patients, 102 were non-diploid, 40 had chromatin heterogeneity, and 126 had a low stroma fraction, respectively. Univariable analysis suggested that non-diploidy was associated with a significantly lower 5-year DFS rate. After combining DNA ploidy and nucleotyping for risk stratification and adjusting for potential confounders, the DNA ploidy and nucleotyping (PN) high-risk group and PN medium-risk group had a 4- (95% CI: 1.497-8.754) and 3-fold (95% CI: 1.196-6.380) increase in the risk of disease progression or mortality within 5 years of follow-up, respectively, compared to the PN low-risk group. In PN high-risk patients, adjuvant therapy was associated with a significantly improved 5-year DFS (HR = 0.214, 95% CI: 0.048-0.957, p = 0.027). (4) Conclusions: the non-diploid DNA status and the combination of ploidy and nucleotyping can be useful prognostic indicators to predict long-term outcomes in early-stage NSCLC patients. Additionally, NSCLC patients with non-diploidy and chromatin homogenous status may benefit from adjuvant therapy.
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Affiliation(s)
- Luning Mao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Jianghua Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhongjie Zhang
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Lijun Mao
- My-BioMed Technology (Guangzhou) Co., Ltd., Guangzhou 510000, China
| | - Yuejin Dong
- My-BioMed Technology (Guangzhou) Co., Ltd., Guangzhou 510000, China
| | - Zufeng He
- My-BioMed Technology (Guangzhou) Co., Ltd., Guangzhou 510000, China
| | - Haiyue Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Kaiwen Chi
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yumeng Jiang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Dongmei Lin
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China
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Zhang L, Guan S, Meng F, Teng L, Zhong D. Next-generation sequencing of homologous recombination genes could predict efficacy of platinum-based chemotherapy in non-small cell lung cancer. Front Oncol 2022; 12:1035808. [PMID: 36591485 PMCID: PMC9794762 DOI: 10.3389/fonc.2022.1035808] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 11/14/2022] [Indexed: 12/15/2022] Open
Abstract
Background With the widespread use of next-generation sequencing (NGS) in clinical practice, an increasing number of biomarkers that predict a response to anti-tumor therapy in non-small cell lung cancer (NSCLC) has been identified. However, validated biomarkers that can be used to detect a response to platinum-based chemotherapy remain unavailable. Several studies have suggested that homologous recombination deficiency (HRD) may occur in response to platinum-based chemotherapy in ovarian cancer and breast cancer. However, currently there is a lack of proven and reliable HRD markers that can be used to screen for patients who may benefit from platinum-based chemotherapy, especially in NSCLC. Methods NGS was used to screen for gene mutations, including homologous recombination (HR) genes and common driver gene mutations in NSCLC. Cox regression analysis was performed to identify potential clinicopathological or gene mutation factors associated with survival in patients receiving platinum-based chemotherapy, while Kaplan-Meier analysis with the log-rank test was performed to assess the effect of HR gene mutations on progression-free survival (PFS). Results In a retrospective cohort of 129 patients with advanced NSCLC, 54 who received platinum-based chemotherapy with or without anti-angiogenic therapy were included in the analysis. Univariate and multivariate Cox proportional hazard regression analyses showed that HR gene mutations were associated with platinum-based chemotherapy sensitivity. Efficacy results indicated that the objective response rates (ORR) for patients with BRCA1/2 mutations and BRCA1/2 wild type were 75% and 30.4% (p=0.041), while the median PFS was 7.5 and 5.5 months (hazard ratio [HR], 0.52; 95% CI, 0.27-1.00; p=0.084), respectively. The ORRs of patients with HR gene mutations and HR gene wild type were 60% and 23.6% (p=0.01), and the median PFS was 7.5 and 5.2 months (HR, 0.56; 95% CI, 0.32-0.97; p=0.033), respectively. Conclusions HR gene mutations show potential as promising biomarkers that may predict sensitivity to platinum-based chemotherapy in advanced and metastatic NSCLC.
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Affiliation(s)
- Linlin Zhang
- Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China
| | - Shasha Guan
- Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China
| | - Fanlu Meng
- Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China
| | - Lin Teng
- Hangzhou Jichenjunchuang Medical Laboratory Co. Ltd., Hangzhou, China
| | - Diansheng Zhong
- Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China,*Correspondence: Diansheng Zhong,
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Gao Y, Luo XD, Yang XL, Tu D. Clinical significance of breast cancer susceptibility gene 1 expression in resected non-small cell lung cancer: A meta-analysis. World J Clin Cases 2021; 9:9090-9100. [PMID: 34786391 PMCID: PMC8567518 DOI: 10.12998/wjcc.v9.i30.9090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/25/2021] [Accepted: 09/02/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The clinical significance of breast cancer susceptibility gene 1 (BRCA1) in non-small cell lung cancer (NSCLC) patients undergoing surgery remains unclear up to now.
AIM To explore the relation of BRCA1 expression with clinicopathological characteristics and survival in patients with resected NSCLC.
METHODS EMBASE, PubMed, Web of Science, and The Cochrane Library databases were searched to identify the relevant articles. To assess the correlation between the expression of BRCA1 and clinicopathological characteristics and prognosis of patients with resected NSCLC patients, the combined relative risks or hazard ratios (HRs) with their corresponding 95% confidence intervals [CIs] were estimated.
RESULTS Totally, 11 articles involving 1041 patients were included in the meta-analysis. The results indicated that the expression of BRCA1 was significantly correlated with prognosis of resected NSCLC. Positive BRCA1 expression signified a shorter overall survival (HR = 1.60, 95%CI: 1.25-2.05; P < 0.001) and disease-free survival (HR = 1.78, 95%CI: 1.42-2.23; P < 0.001). However, no significant association of BRCA1 expression with any clinicopathological parameters was observed.
CONCLUSION BRCA1 expression indicates a poor prognosis in resected NSCLC patients. BRCA1 might serve as an independent biomarker to predict clinical outcomes and help to customize optimal adjuvant chemotherapy for NSCLC patients who had received surgical therapy.
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Affiliation(s)
- Yang Gao
- Department of Cardiothoracic Surgery, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming 650032, Yunnan Province, China
| | - Xiao-Di Luo
- Department of Cardiothoracic Surgery, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming 650032, Yunnan Province, China
| | - Xiao-Li Yang
- Department of Cardiothoracic Surgery, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming 650032, Yunnan Province, China
| | - Dong Tu
- Department of Cardiothoracic Surgery, 920th Hospital of Joint Logistics Support Force of People’s Liberation Army of China, Kunming 650032, Yunnan Province, China
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Novello S, Torri V, Grohe C, Kurz S, Serke M, Wehler T, Meyer A, Ladage D, Geissler M, Colantonio I, Cauchi C, Stoelben E, Ceribelli A, Kropf-Sanchen C, Valmadre G, Borra G, Schena M, Morabito A, Santo A, Gregorc V, Chiari R, Reck M, Schmid-Bindert G, Folprecht G, Griesinger F, Follador A, Pedrazzoli P, Bearz A, Caffo O, Dickgreber NJ, Irtelli L, Wiest G, Monica V, Porcu L, Manegold C, Scagliotti GV. International Tailored Chemotherapy Adjuvant (ITACA) trial, a phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy versus standard adjuvant chemotherapy in completely resected stage II-IIIA non-small-cell lung cancer. Ann Oncol 2021; 33:57-66. [PMID: 34624497 DOI: 10.1016/j.annonc.2021.09.017] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 09/05/2021] [Accepted: 09/26/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor. PATIENTS AND METHODS Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS). RESULTS Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T. CONCLUSION In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.
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Affiliation(s)
- S Novello
- Department of Oncology at San Luigi Hospital, University of Torino, Orbassano (Torino), Italy.
| | - V Torri
- Laboratory of Methodology for Clinical Research, Oncology Department at Instituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - C Grohe
- Department of Respiratory Diseases, Evangelische Lungenklinik Berlin, Berlin, Germany
| | - S Kurz
- Evangelische Lungenklinik Berlin, Berlin, Germany
| | - M Serke
- Thorax Center Clinic for Haematology, Oncology, Pulmonology and Palliative Medicine, Evangelisches Krankenhaus Hamm, Hamm, Germany
| | - T Wehler
- Thorax Center Clinic for Haematology, Oncology, Pulmonology and Palliative Medicine, Evangelisches Krankenhaus Hamm, Hamm, Germany
| | - A Meyer
- Department of Pneumology, Maria Hilf Hospital, Moenchengladbach, Germany
| | - D Ladage
- Department of Pneumology, Maria Hilf Hospital, Moenchengladbach, Germany
| | - M Geissler
- Esslingen Cancer Center Department of Oncology, Gastroenterology and Infectious Diseases Klinikum Esslingen, Esslingen, Germany
| | - I Colantonio
- Division of Oncology, Azienda Ospedaliera Santa Croce e Carle, Cuneo, Italy
| | - C Cauchi
- Division of Oncology, Azienda Ospedaliera Santa Croce e Carle, Cuneo, Italy
| | - E Stoelben
- Lung Clinic, Cologne-Merheim Hospital, Cologne, Germany
| | - A Ceribelli
- Division of Clinical Oncology A, Istituto Nazionale Regina Elena per lo Studio e la Cura dei Tumori, Rome, Italy
| | - C Kropf-Sanchen
- Department of Pulmonology, Internal Medicine II, University of Ulm, Ulm, Germany
| | - G Valmadre
- Division of Clinical Oncology, Ospedale di Sondalo, Sondrio, Italy
| | - G Borra
- Division of Clinical Oncology, AOU Maggiore della Carità, Novara, Italy
| | - M Schena
- Division of Clinical Oncology I, AOU Città della Salute e della Scienza, Turin, Italy
| | - A Morabito
- Division of Clinical Oncology and Thoracic Pneumology, IRCCS Fondazione Pascale, Naples, Italy
| | - A Santo
- Complex Operative Unit of Oncology - Gruppo Interdisciplinare Veronese Oncologia Polmonare (GIVOP), Verona, Italy
| | - V Gregorc
- Division of Clinical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy
| | - R Chiari
- Division of Clinical Oncology, Azienda Ospedaliera di Perugia, Ospedale Santa Maria della Misericordia, Perugia, Italy
| | - M Reck
- Oncology Department, LungenClinic Grosshansdorf, Grosshansdorf, Germany
| | - G Schmid-Bindert
- Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - G Folprecht
- University Hospital Carl Gustav Carus Medical Department I Dresden, Dresden, Germany
| | - F Griesinger
- Clinic for Haematology and Oncoloy, Medizinischer Campus Universität Oldenburg, Oldenburg, Germany
| | - A Follador
- Department of Oncology, Presidio Ospedaliero Universitario Santa Maria della Misericordia, Azienda Sanitaria Universitaria Integrata Friuli Centrale, Udine, Italy
| | - P Pedrazzoli
- Oncology Division, University Hospital Santa Maria della Misericordia AOU Friuli Centrale, Udine, Italy
| | - A Bearz
- Division of Clinical Oncology, Centro di Riferimento Oncologico, Aviano, Italy
| | - O Caffo
- Division of Clinical Oncology, Ospedale Santa Chiara, Trento, Italy
| | - N J Dickgreber
- Department for Respiratory Medicine and Thoracic Oncology, Klinikum Rheine - Mathias-Spital, Rheine, Germany
| | - L Irtelli
- Oncology Clinic, Policlinico SS. Annunziata, Chieti, Italy
| | - G Wiest
- Asklepios Cancer Center Hamburg, Asklepios Klinikum Harburg, Hamburg, Harburg, Germany
| | - V Monica
- Department of Oncology at San Luigi Hospital, University of Torino, Orbassano (Torino), Italy
| | - L Porcu
- Laboratory of Methodology for Clinical Research, Oncology Department at Instituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - C Manegold
- Department of Surgery, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
| | - G V Scagliotti
- Department of Oncology at San Luigi Hospital, University of Torino, Orbassano (Torino), Italy
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Liu GY, Zhang W, Chen XC, Wu WJ, Wan SQ. Diagnostic and Prognostic Significance of Keap1 mRNA Expression for Lung Cancer Based on Microarray and Clinical Information from Oncomine Database. Curr Med Sci 2021; 41:597-609. [PMID: 34169426 DOI: 10.1007/s11596-021-2378-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/21/2021] [Indexed: 11/29/2022]
Abstract
We performed a bioinformatics analysis with validation by multiple databases, aiming to evaluate the diagnostic and prognostic value of Kelch-like ECH-associated protein 1 (Keap1) mRNA for lung cancer, and to explore possible mechanisms. Diagnostic performance of Keap1 mRNA was determined by receiver operating characteristic (ROC) curve analysis. Prognostic implication of Keap1 mRNA was estimated by Kaplan-Meier survival analysis. Co-expressed genes with both Keap1 and Nfe2L2 were identified by LinkedOmics. Mechanisms of Keap1-Nfe2L2-co-expressed genes underlying the pathogenesis of lung cancer were explored by function enrichment and pathway analysis. The ROC curve analysis determined a good diagnostic performance of Keap1 mRNA for lung squamous cell carcinoma (LUSC), with an area under the ROC curve (AUC) of 0.833, sensitivity of 72.7%, and specificity of 90.6% (P<0.001). Multivariate Cox regression recognized high Keap1 mRNA to be an independent risk factor of mortality for overall lung cancer [hazard ratio (HR): 11.034, P=0.044], but an independent antagonistic factor for lung adenocarcinoma (LUAD) (HR: 0.404, P<0.001). Validation by UALCAN and GEPIA supported Oncomine findings regarding the diagnostic value of Keap1 mRNA for LUSC, but denied its prognostic value. After screening, we identified 17 co-expressed genes with both Keap1 and Nfe2L2 for LUAD, and 22 for LUSC, mainly enriched in signaling pathway of oxidative stress-induced gene expression via Nrf2. In conclusion, Keap1 mRNA has a good diagnostic performance, but controversial prognostic efficacy for LUSC. The pathogenesis of lung cancer is associated with Keap1-Nfe2L2-co-expressed genes by signaling pathway of oxidative stress-induced gene expression via Nrf2.
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Affiliation(s)
- Guang-Ya Liu
- Department of Infectious Diseases, Wuhan Jinyintan Hospital, Wuhan, 430023, China
| | - Wei Zhang
- Department of Critical Care Medicine, Wuhan Jinyintan Hospital, Wuhan, 430023, China
| | - Xu-Chi Chen
- Department of Critical Care Medicine, Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, 430063, China
| | - Wen-Juan Wu
- Department of Critical Care Medicine, Wuhan Jinyintan Hospital, Wuhan, 430023, China
| | - Shi-Qian Wan
- Department of Infectious Diseases, Wuhan Jinyintan Hospital, Wuhan, 430023, China.
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Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy. J Pers Med 2021; 11:jpm11050389. [PMID: 34068585 PMCID: PMC8151497 DOI: 10.3390/jpm11050389] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/05/2021] [Accepted: 05/06/2021] [Indexed: 12/04/2022] Open
Abstract
ATM and BRCA1 are DNA repair genes that play a central role in homologous recombination repair. Alterations of ATM and BRCA1 gene expression are found in cancers, some of which are correlated with treatment response and patient outcome. However, the role of ATM and BRCA1 gene expression in head and neck cancer (HNC) is not well characterized. Here, we examined the prognostic role of ATM and BRCA1 expression in two HNC cohorts with and without betel quid (BQ) exposure. The results showed that the expression of ATM and BRCA1 was downregulated in BQ-associated HNC, as the BQ ingredient arecoline could suppress the expression of both genes. Low expression of either ATM or BRCA1 was correlated with poor overall survival (OS) and was an independent prognostic factor in multivariate analysis (ATM HR: 1.895, p = 0.041; BRCA1 HR: 2.163, p = 0.040). The combination of ATM and BRCA1 expression states further improved on the prediction of OS (HR: 4.195, p = 0.001, both low vs. both high expression). Transcriptomic analysis showed that inhibition of ATM kinase by KU55933 induced apoptosis signaling and potentiated cisplatin-induced cytotoxicity. These data unveil poor prognosis in the HNC patient subgroup with low expression of ATM and BRCA1 and support the notion of ATM-targeted therapy.
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Climent M, Viggiani G, Chen YW, Coulis G, Castaldi A. MicroRNA and ROS Crosstalk in Cardiac and Pulmonary Diseases. Int J Mol Sci 2020; 21:ijms21124370. [PMID: 32575472 PMCID: PMC7352701 DOI: 10.3390/ijms21124370] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/14/2020] [Accepted: 06/16/2020] [Indexed: 12/12/2022] Open
Abstract
Reactive oxygen species (ROS) affect many cellular functions and the proper redox balance between ROS and antioxidants contributes substantially to the physiological welfare of the cell. During pathological conditions, an altered redox equilibrium leads to increased production of ROS that in turn may cause oxidative damage. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level contributing to all major cellular processes, including oxidative stress and cell death. Several miRNAs are expressed in response to ROS to mediate oxidative stress. Conversely, oxidative stress may lead to the upregulation of miRNAs that control mechanisms to buffer the damage induced by ROS. This review focuses on the complex crosstalk between miRNAs and ROS in diseases of the cardiac (i.e., cardiac hypertrophy, heart failure, myocardial infarction, ischemia/reperfusion injury, diabetic cardiomyopathy) and pulmonary (i.e., idiopathic pulmonary fibrosis, acute lung injury/acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, lung cancer) compartments. Of note, miR-34a, miR-144, miR-421, miR-129, miR-181c, miR-16, miR-31, miR-155, miR-21, and miR-1/206 were found to play a role during oxidative stress in both heart and lung pathologies. This review comprehensively summarizes current knowledge in the field.
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Affiliation(s)
- Montserrat Climent
- Humanitas Clinical and Research Center—IRCCS, Via Manzoni 56, 20089 Rozzano, MI, Italy;
| | - Giacomo Viggiani
- Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, MI, Italy;
| | - Ya-Wen Chen
- Hastings Center for Pulmonary Research and Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
- Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Gerald Coulis
- Department of Physiology and Biophysics, and Institute for Immunology, University of California Irvine, Irvine, CA 92697, USA;
| | - Alessandra Castaldi
- Hastings Center for Pulmonary Research and Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA;
- Correspondence:
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Identification of PDL1-Related Biomarkers to Select Lung Adenocarcinoma Patients for PD1/PDL1 Inhibitors. DISEASE MARKERS 2020; 2020:7291586. [PMID: 32587640 PMCID: PMC7303743 DOI: 10.1155/2020/7291586] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 03/15/2020] [Accepted: 05/25/2020] [Indexed: 12/23/2022]
Abstract
PD1/PDL1 inhibitors have been adopted for the treatment of advanced non-small-cell lung cancer, and PDL1 expression has been investigated as a predictive biomarker for PD1/PDL1 inhibitor therapy. However, PDL1 lacks diagnostic accuracy in differentiating patients who are likely or unlikely to benefit. So, it is urgent and clinically significant to identify other associated predictive biomarkers for PD1/PDL1 inhibitor therapy. Our work was to identify PDL1-related biomarkers that could improve the patient selection for PD1/PDL1 inhibitor treatment. We obtained 500 genes coexpressed with PDL1 in lung adenocarcinoma from the TCGA database. Then, we identified 125 out of 500 genes differentially expressed in lung adenocarcinoma. A total of 39 genes were distinguished with prognostic value and associated with overall survival. Median survival time analysis based on gene expression level, protein-protein interaction analysis, GO and KEGG enrichment analyses, and significant GO and KEGG function consistency analyses were conducted to screen candidate biomarkers. Three candidate genes, BRCA1, BRIP1, and EREG, were identified to be functionally significantly coexpressed with PDL1. Functional enrichment analysis and protein-protein interaction networks further showed that these genes mainly participated in immune response and cell activation. Additionally, to find potential adjuvant therapeutic targets in PD1/PDL1 inhibitor treatment, we performed transcription factor prediction analysis. A group of negative differential expression but PDL1-related biomarkers has been identified, which might help to assess the clinical management of lung cancer patients. A combination of potential biomarkers and adjuvant therapeutic targets with PDL1 will predict the response to PD1/PDL1 inhibitors more accurately and help with the patient selection for more personalized immune checkpoint inhibitor treatment.
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11
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Huang M, Chen Y, Han D, Lei Z, Chu X. Role of the zinc finger and SCAN domain-containing transcription factors in cancer. Am J Cancer Res 2019; 9:816-836. [PMID: 31218096 PMCID: PMC6556609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Accepted: 04/04/2019] [Indexed: 06/09/2023] Open
Abstract
Transcription factors are key determinants of gene expression that recognize and bind to short DNA sequence motifs, thereby regulating many biological processes including differentiation, development, and metabolism. Transcription factors are increasingly recognized for their roles in cancer progression. Here, we describe a subfamily of zinc finger transcription factors named zinc finger and SCAN domain containing (ZSCAN) transcription factors. In this review, we summarize the identified members of the ZSCAN family of transcription factors and their roles in cancer progression. Due to the complex regulation mechanisms, ZSCAN transcription factors may show promotive or prohibitive efforts in angiogenesis, cell apoptosis, cell differentiation, cell migration and invasion, cell proliferation, stem cell properties, and chemotherapy sensitivity. The upstream regulation mechanisms of their varied expression levels may include gene mutation, DNA methylation, alternative splicing, and miRNA regulation. What's more, to clarify their diverse functions, we summarize the modulation mechanisms of their activity in downstream genes transcription, including protein-protein interactions mediated by their SCAN box, recruitment of co-regulating molecules and post-translational modifications. A better understanding of the widespread regulatory mode of these transcription factors will provide further insight into the mechanism of transcriptional regulation and suggest novel therapeutic strategies against tumor progression.
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Affiliation(s)
- Mengxi Huang
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing UniversityNanjing, Jiangsu Province, People’s Republic of China
| | - Yanyan Chen
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing UniversityNanjing, Jiangsu Province, People’s Republic of China
| | - Dong Han
- Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical UniversityNanjing, Jiangsu Province, People’s Republic of China
| | - Zengjie Lei
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing UniversityNanjing, Jiangsu Province, People’s Republic of China
- Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical UniversityNanjing, Jiangsu Province, People’s Republic of China
| | - Xiaoyuan Chu
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing UniversityNanjing, Jiangsu Province, People’s Republic of China
- Department of Medical Oncology, Jinling Hospital, Nanjing Clinical School of Southern Medical UniversityNanjing, Jiangsu Province, People’s Republic of China
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12
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Moes-Sosnowska J, Rzepecka IK, Chodzynska J, Dansonka-Mieszkowska A, Szafron LM, Balabas A, Lotocka R, Sobiczewski P, Kupryjanczyk J. Clinical importance of FANCD2, BRIP1, BRCA1, BRCA2 and FANCF expression in ovarian carcinomas. Cancer Biol Ther 2019; 20:843-854. [PMID: 30822218 PMCID: PMC6606037 DOI: 10.1080/15384047.2019.1579955] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE DNA repair pathways are potential targets of molecular therapy in cancer patients. The FANCD2, BRIP1, BRCA1/2, and FANCF genes are involved in homologous recombination DNA repair, which implicates their possible role in cell response to DNA-damaging agents. We evaluated a clinical significance of pre-treatment expression of these genes at mRNA level in 99 primary, advanced-stage ovarian carcinomas from patients, who later received taxane-platinum (TP) or platinum-cyclophosphamide (PC) treatment. METHODS Gene expression was determined with the use of Real-Time PCR. The BRCA2 and BRIP1 gene sequence was investigated with the use of SSCP, dHPLC, and PCR-sequencing. RESULTS Increased FANCD2 expression occurred to be a negative prognostic factor for all patients (PC+TP:HR 3.85, p = 0.0003 for the risk of recurrence; HR 1.96, p = 0.02 for the risk of death), and this association was even stronger in the TP-treated group (HR 6.7, p = 0.0002 and HR 2.33, p = 0.01, respectively). Elevated BRIP1 expression was the only unfavorable molecular factor in the PC-treated patients (HR 8.37, p = 0.02 for the risk of recurrence). Additionally, an increased FANCD2 and BRCA1/2 expression levels were associated with poor ovarian cancer outcome in either TP53-positive or -negative subgroups of the TP-treated patients, however these groups were small. Sequence analysis identified one protein truncating variant (1/99) in BRCA2 and no mutations (0/56) in BRIP1. CONCLUSIONS Our study shows for the first time that FANCD2 overexpression is a strong negative prognostic factor in ovarian cancer, particularly in patients treated with TP regimen. Moreover, increased mRNA level of the BRIP1 is a negative prognostic factor in the PC-treated patients. Next, changes in the BRCA2 and BRIP1 genes are rare and together with other analyzed FA genes considered as homologous recombination deficiency may not affect the expression level of analyzed genes.
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Affiliation(s)
- Joanna Moes-Sosnowska
- a Department of Immunology , Maria Sklodowska-Curie Institute - Oncology Center , Warsaw , Poland
| | - Iwona K Rzepecka
- b Department of Pathology and Laboratory Diagnostics , Maria Sklodowska-Curie Institute - Oncology Center , Warsaw , Poland
| | - Joanna Chodzynska
- c Laboratory of Bioinformatics and Biostatistics , Maria Sklodowska-Curie Institute - Oncology Center , Warsaw , Poland
| | - Agnieszka Dansonka-Mieszkowska
- b Department of Pathology and Laboratory Diagnostics , Maria Sklodowska-Curie Institute - Oncology Center , Warsaw , Poland
| | - Lukasz M Szafron
- a Department of Immunology , Maria Sklodowska-Curie Institute - Oncology Center , Warsaw , Poland
| | - Aneta Balabas
- d Department of Genetics , Maria Sklodowska-Curie Institute - Oncology Center , Warsaw , Poland
| | - Renata Lotocka
- b Department of Pathology and Laboratory Diagnostics , Maria Sklodowska-Curie Institute - Oncology Center , Warsaw , Poland
| | - Piotr Sobiczewski
- e Department of Gynecologic Oncology , Maria Sklodowska-Curie Institute - Oncology Center , Warsaw , Poland
| | - Jolanta Kupryjanczyk
- b Department of Pathology and Laboratory Diagnostics , Maria Sklodowska-Curie Institute - Oncology Center , Warsaw , Poland
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13
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Tessari A, Parbhoo K, Pawlikowski M, Fassan M, Rulli E, Foray C, Fabbri A, Embrione V, Ganzinelli M, Capece M, Campbell MJ, Broggini M, La Perle K, Farina G, Cole S, Marabese M, Hernandez M, Amann JM, Pruneri G, Carbone DP, Garassino MC, Croce CM, Palmieri D, Coppola V. RANBP9 affects cancer cells response to genotoxic stress and its overexpression is associated with worse response to platinum in NSCLC patients. Oncogene 2018; 37:6463-6476. [PMID: 30076413 PMCID: PMC6690599 DOI: 10.1038/s41388-018-0424-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 06/28/2018] [Accepted: 07/05/2018] [Indexed: 01/11/2023]
Abstract
Although limited by severe side effects and development of resistance, platinum-based therapies still represent the most common first-line treatment for non-small cell lung cancer (NSCLC). However, a crucial need in the clinical management of NSCLC is represented by the identification of cases sensitive to DNA damage response (DDR)-targeting drugs, such as cisplatin or PARP inhibitors. Here, we provide a molecular rationale for the stratification of NSCLC patients potentially benefitting from platinum compounds based on the expression levels of RANBP9, a recently identified player of the cellular DDR. RANBP9 was found overexpressed by immunohistochemistry (IHC) in NSCLC compared to normal adjacent tissues (NATs) (n = 147). Moreover, a retrospective analysis of 132 platinum-treated patients from the multi-centric TAILOR trial showed that RANBP9 overexpression levels are associated with clinical response to platinum compounds [Progression Free Survival Hazard Ratio (RANBP9 high vs low) 1.73, 95% CI 1.15-2.59, p = 0.0084; Overall Survival HR (RANBP9 high vs low) 1.99, 95% CI 1.27-3.11, p = 0.003]. Accordingly, RANBP9 KO cells showed higher sensitivity to cisplatin in comparison with WT controls both in vitro and in vivo models. NSCLC RANBP9 KO cells were also more sensitive than control cells to the PARP inhibitor olaparib alone and in combination with cisplatin, due to defective ATM-dependent and hyper-activated PARP-dependent DDR. The current investigation paves the way to prospective studies to assess the clinical value of RANBP9 protein levels as prognostic and predictive biomarker of response to DDR-targeting drugs, leading to the development of new tools for the management of NSCLC patients.
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Affiliation(s)
- Anna Tessari
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Kareesma Parbhoo
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Meghan Pawlikowski
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy
| | - Eliana Rulli
- Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Claudia Foray
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Alessandra Fabbri
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Valerio Embrione
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Monica Ganzinelli
- Thoracic Oncology Unit, Department of Medical Oncology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | - Marina Capece
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Moray J Campbell
- Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, 536 Parks Hall, Columbus, OH, 43210, USA
| | - Massimo Broggini
- Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Krista La Perle
- Department of Veterinary Biosciences and Comparative Pathology and Mouse Phenotyping Shared Resource, College of Veterinary Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, USA
| | - Gabriella Farina
- Department of Oncology, Ospedale Fatebenefratelli and Oftalmico, Milan, Italy
| | - Sara Cole
- Campus Microscopy and Imaging Facility, The Ohio State University, Columbus, OH, 43210, USA
| | - Mirko Marabese
- Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
| | - Marianna Hernandez
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Joseph M Amann
- Department of Internal Medicine, College of Medicine, James Thoracic Center, Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Giancarlo Pruneri
- Division of Pathology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | - David P Carbone
- Department of Internal Medicine, College of Medicine, James Thoracic Center, Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Marina C Garassino
- Thoracic Oncology Unit, Department of Medical Oncology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | - Carlo M Croce
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Dario Palmieri
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Vincenzo Coppola
- Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA.
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14
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Moon DH, Kwon SO, Kim WJ, Hong Y. Identification of Serial DNA Methylation Changes in the Blood Samples of Patients with Lung Cancer. Tuberc Respir Dis (Seoul) 2018; 82:126-132. [PMID: 30302959 PMCID: PMC6435926 DOI: 10.4046/trd.2018.0042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Revised: 06/21/2018] [Accepted: 07/31/2018] [Indexed: 12/21/2022] Open
Abstract
Background The development of lung cancer results from the interaction between genetic mutations and dynamic epigenetic alterations, although the exact mechanisms are not completely understood. Changes in DNA methylation may be a promising biomarker for early detection and prognosis of lung cancer. We evaluated the serial changes in genome-wide DNA methylation patterns in blood samples of lung cancer patients. Methods Blood samples were obtained for three consecutive years from three patients (2 years before, 1 year before, and after lung cancer detection) and from three control subjects (without lung cancer). We used the MethylationEPIC BeadChip method, which covers the 850,000 bp cytosine-phosphate-guanine (CpG) site, to conduct an epigenome-wide analysis. Significant differentially methylated regions (DMRs) were identified using p-values <0.05 in a correlation test identifying serial methylation changes and serial increase or decrease in β value above 0.1 for three consecutive years. Results We found three significant CpG sites with differentially methylated β values and 7,105 CpG sites with significant correlation from control patients without lung cancer. However, there were no significant DMRs. In contrast, we found 11 significant CpG sites with differentially methylated β values and 10,562 CpG sites with significant correlation from patients with lung cancer. There were two significant DMRs: cg21126229 (RNF212) and cg27098574 (BCAR1). Conclusion This study revealed DNA methylation changes that might be implicated in lung cancer development. The DNA methylation changes may be the possible candidate target regions for the early detection and prevention of lung cancer.
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Affiliation(s)
- Da Hye Moon
- Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Korea
| | - Sung Ok Kwon
- Biomedical Research Institute, Kangwon National University Hospital, Chuncheon, Korea
| | - Woo Jin Kim
- Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Korea.,Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Yoonki Hong
- Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Korea.,Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea.
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15
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Lee RC, Thapa B, John T. LACES and bootstraps: the hunt for prognostic and predictive markers for adjuvant therapy in NSCLC. Transl Lung Cancer Res 2018; 7:S239-S242. [PMID: 30393612 PMCID: PMC6193923 DOI: 10.21037/tlcr.2018.09.01] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 09/03/2018] [Indexed: 12/29/2022]
Affiliation(s)
- Rachael Chang Lee
- Olivia Newton-John Cancer Centre, Austin Health, Melbourne, Australia
| | - Bibhusal Thapa
- Olivia Newton-John Cancer Centre, Austin Health, Melbourne, Australia
| | - Thomas John
- Olivia Newton-John Cancer Centre, Austin Health, Melbourne, Australia
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16
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Martínez-Terroba E, Behrens C, de Miguel FJ, Agorreta J, Monsó E, Millares L, Sainz C, Mesa-Guzman M, Pérez-Gracia JL, Lozano MD, Zulueta JJ, Pio R, Wistuba II, Montuenga LM, Pajares MJ. A novel protein-based prognostic signature improves risk stratification to guide clinical management in early-stage lung adenocarcinoma patients. J Pathol 2018; 245:421-432. [PMID: 29756233 DOI: 10.1002/path.5096] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Revised: 04/18/2018] [Accepted: 05/03/2018] [Indexed: 12/14/2022]
Abstract
Each of the pathological stages (I-IIIa) of surgically resected non-small-cell lung cancer has hidden biological heterogeneity, manifested as heterogeneous outcomes within each stage. Thus, the finding of robust and precise molecular classifiers with which to assess individual patient risk is an unmet medical need. Here, we identified and validated the clinical utility of a new prognostic signature based on three proteins (BRCA1, QKI, and SLC2A1) to stratify early-stage lung adenocarcinoma patients according to their risk of recurrence or death. Patients were staged according to the new International Association for the Study of Lung Cancer (IASLC) staging criteria (8th edition, 2018). A test cohort (n = 239) was used to assess the value of this new prognostic index (PI) based on the three proteins. The prognostic signature was developed by Cox regression with the use of stringent statistical criteria (TRIPOD: Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis). The model resulted in a highly significant predictor of 5-year outcome for disease-free survival (p < 0.001) and overall survival (p < 0.001). The prognostic ability of the model was externally validated in an independent multi-institutional cohort of patients (n = 114, p = 0.021). We also demonstrated that this molecular classifier adds relevant information to the gold standard TNM-based pathological staging, with a highly significant improvement of the likelihood ratio. We subsequently developed a combined PI including both the molecular and the pathological data that improved the risk stratification in both cohorts (p ≤ 0.001). Moreover, the signature may help to select stage I-IIA patients who might benefit from adjuvant chemotherapy. In summary, this protein-based signature accurately identifies those patients with a high risk of recurrence and death, and adds further prognostic information to the TNM-based clinical staging, even when the new IASLC 8th edition staging criteria are applied. More importantly, it may be a valuable tool for selecting patients for adjuvant therapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Elena Martínez-Terroba
- Program in Solid Tumours, CIMA, Pamplona, Spain.,Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain
| | - Carmen Behrens
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Fernando J de Miguel
- Program in Solid Tumours, CIMA, Pamplona, Spain.,Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Jackeline Agorreta
- Program in Solid Tumours, CIMA, Pamplona, Spain.,Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.,Navarra Health Research Institute (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Eduard Monsó
- Respiratory Diseases Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain.,Ciber de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain
| | - Laura Millares
- Respiratory Diseases Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain.,Ciber de Enfermedades Respiratorias - CIBERES, Instituto de Salud Carlos III, Madrid, Spain
| | - Cristina Sainz
- Program in Solid Tumours, CIMA, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Miguel Mesa-Guzman
- Navarra Health Research Institute (IDISNA), Pamplona, Spain.,Department of Thoracic Surgery, Clínica Universidad de Navarra, Pamplona, Spain
| | - José Luis Pérez-Gracia
- Navarra Health Research Institute (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.,Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain
| | - María Dolores Lozano
- Navarra Health Research Institute (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.,Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Javier J Zulueta
- Navarra Health Research Institute (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.,Department of Neumology, Clínica Universidad de Navarra, Pamplona, Spain
| | - Ruben Pio
- Program in Solid Tumours, CIMA, Pamplona, Spain.,Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.,Navarra Health Research Institute (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Ignacio I Wistuba
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Translational Molecular Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Luis M Montuenga
- Program in Solid Tumours, CIMA, Pamplona, Spain.,Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.,Navarra Health Research Institute (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - María J Pajares
- Program in Solid Tumours, CIMA, Pamplona, Spain.,Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.,Navarra Health Research Institute (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
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17
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Xu Y, Wang Y, Liu H, Kang X, Li W, Wei Q. Genetic variants of genes in the Notch signaling pathway predict overall survival of non-small cell lung cancer patients in the PLCO study. Oncotarget 2018; 7:61716-61727. [PMID: 27557513 PMCID: PMC5308685 DOI: 10.18632/oncotarget.11436] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 08/11/2016] [Indexed: 12/17/2022] Open
Abstract
The Notch signaling pathway has been shown to have biological significance and therapeutic application in non-small cell lung cancer (NSCLC). We hypothesize that genetic variants of genes in the Notch signaling pathway are associated with overall survival (OS) of NSCLC patients. To test this hypothesis, we performed multivariate Cox proportional hazards regression analysis to evaluate associations of 19,571 single nucleotide polymorphisms (SNPs) in 132 Notch pathway genes with OS of 1,185 NSCLC patients available from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that five potentially functional tagSNPs in four genes (i.e., ADAM12 rs10794069 A > G, DTX1 rs1732793 G > A, TLE1 rs199731120 C > CA, TLE1 rs35970494 T > TC and E2F3 rs3806116 G > T) were associated with a poor OS, with a variant-allele attributed hazards ratio (HR) of 1.27 [95% confidence interval (95% CI) = 1.13–1.42, P = 3.62E-05], 1.30 (1.14–1.49, 8.16E-05), 1.40 (1.16–1.68, 3.47E-04), 1.27 (1.11–1.44, 3.38E-04), and 1.21 (1.09–1.33, 2.56E-04), respectively. Combined analysis of these five risk genotypes revealed that the genetic score 0–5 was associated with the adjusted HR in a dose-response manner (Ptrend = 3.44E-13); individuals with 2–5 risk genotypes had an adjusted HR of 1.56 (1.34–1.82, 1.46E-08), compared with those with 0–1 risk genotypes. Larger studies are needed to validate our findings.
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Affiliation(s)
- Yinghui Xu
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.,Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.,Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Yanru Wang
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.,Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Hongliang Liu
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.,Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Xiaozheng Kang
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.,Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Department of Thoracic Surgery I, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Wei Li
- Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China
| | - Qingyi Wei
- Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA.,Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
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18
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Association of BRCA1, ERCC1, RAP80, PKM2, RRM1, RRM2, TS, TSP1, and TXR1 mRNA expression levels between primary tumors and infiltrated regional lymph nodes in patients with resectable non-small cell lung cancer. THE PHARMACOGENOMICS JOURNAL 2018; 19:15-24. [PMID: 29472587 DOI: 10.1038/s41397-018-0013-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 10/02/2017] [Accepted: 12/04/2017] [Indexed: 12/23/2022]
Abstract
Differences in gene expression levels between the primary tumors (PTs) and matched regional lymph nodal metastases (LNs) in patients with totally excised non-small cell lung cancer (NSCLC) were explored. Microdissected formalin-fixed paraffin-embedded (FFPE) samples from (PT) and their matched infiltrated LNs, from 239 patients [183 (with matched PT and LNs samples)-case and 56 PT only samples-control cohorts] were analyzed for BRCA1, ERCC1, RAP80, PKM2, RRM1, RRM2, TS, TSP1, and TXR1 mRNA expression by quantitative real-time polymerase-chain reaction (PCR). Moderately positive correlation between the expression of each gene in the PT and the matched LNs was observed. Concordance rates between the PT and the LNs were: BRCA1 (67.7%), ERCC1 (68.4%), PKM2 (63.4%), RAP80 (68.8%), RRM1 (70.9%), RRM2 (69%), TS (72.9%), TSP1 (69.8%), TXR1 (63.7%). Expression levels and their differences were correlated with Relapse-Free Survival (RFS) and Overall Survival (OS). High BRCA1 PT in patients with squamous histology was associated with increased OS (p = 0.036). High TSP1 PT levels were shown to be the only independent prognostic factor for OS and RFS (p = 0.023 and p = 0.007). PKM2 low levels in both PT and matched LNs were associated with better OS irrespective of the underlying histology (p = 0.031). RRM1 discordant levels between PT and matched LNs were associated with worse OS in squamous tumors (p = 0.019) compared to patients with both low expression in PT and LN.TXR1 high levels in both PT and matched LNs were associated with better OS in patients with squamous tumors (p = 0.007).These findings indicate that there is different gene expression between PT and matched LNs which may affect the outcome in early NSCLC and therefore PT's molecular biology should not be the sole determinant for prognostication.
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MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early-stage lung cancer patients from the IFCT-0002 Phase 3 Trial. Oncotarget 2018; 8:4313-4329. [PMID: 28008145 PMCID: PMC5354834 DOI: 10.18632/oncotarget.14025] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 12/05/2016] [Indexed: 12/25/2022] Open
Abstract
Introduction DNA repair is a double-edged sword in lung carcinogenesis. When defective, it promotes genetic instability and accumulated genetic alterations. Conversely these defects could sensitize cancer cells to therapeutic agents inducing DNA breaks. Methods We used immunohistochemistry (IHC) to assess MSH2, XRCC5, and BRCA1 expression in 443 post-chemotherapy specimens from patients randomized in a Phase 3 trial, comparing two neoadjuvant regimens in 528 Stage I-II non-small cell lung cancer (NSCLC) patients (IFCT-0002). O6MGMT promoter gene methylation was analyzed in a subset of 208 patients of the same trial with available snap-frozen specimens. Results Median follow-up was from 90 months onwards. Only high BRCA1 (n = 221, hazard ratio [HR] = 1.58, 95% confidence interval [CI] [1.07-2.34], p = 0.02) and low MSH2 expression (n = 356, HR = 1.52, 95% CI [1.11-2.08], p = 0.008) significantly predicted better overall survival (OS) in univariate and multivariate analysis. A bootstrap re-sampling strategy distinguished three patient groups at high (n = 55, low BRCA1 and high MSH2, median OS >96 months, HR = 2.5, 95% CI [1.45-4.33], p = 0.001), intermediate (n = 82, median OS = 73.4 p = 0.0596), and low (high BRCA1 and low MSH2, n = 67, median OS = ND, HR = 0.51, 95% CI [0.31-0.83], p = 0.006) risk of death. Interpretation DNA repair protein expression assessment identified three different groups of risk of death in early-stage lung cancer patients, according to their tumor MSH2 and BRCA1 expression levels. These results deserve prospective evaluation of MSH2/BRCA1 theranostic value in lung cancer patients treated with combinations of DNA-damaging chemotherapy and drugs targeting DNA repair, such as Poly(ADP-ribose) polymerase (PARP) inhibitors.
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20
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Zhong J, Zheng Q, Gao E, Dong Z, Zhao J, An T, Wu M, Zhuo M, Wang Y, Li J, Wang S, Yang X, Chen H, Jia B, Wang J, Wang Z. Influence of body mass index on the therapeutic efficacy of gemcitabine plus cisplatin and overall survival in lung squamous cell carcinoma. Thorac Cancer 2018; 9:291-297. [PMID: 29318765 PMCID: PMC5792736 DOI: 10.1111/1759-7714.12581] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 11/26/2017] [Accepted: 11/26/2017] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Gemcitabine plus cisplatin (GP) is commonly used to treat lung squamous cell carcinoma (SCC); however, it is not clear which subgroup of lung SCC patients could benefit most from GP treatment. We explored the predictive factors in lung SCC patient cohorts. METHODS Seventy-eight lung SCC patients treated with a first-line GP regimen were enrolled in this retrospective cohort study. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Classification tree models were used to explore the risk factors for PFS and OS in these patients. RESULTS The median PFS and OS in SCC patients treated with a GP regimen were 6.0 and 13.6 months, respectively. Three terminal subgroups were formed for both PFS and OS. The subgroup with a body mass index (BMI) > 23.94 kg/m2 and aged ≤ 54.5 had the longest PFS (9.0 months); the subgroup with a BMI < 23.94 kg/m2 and aged ≤ 54.5 had the shortest PFS (4.05 months). Patients with an objective response (partial or complete response) to treatment had the longest OS (20.0 months), while patients with a BMI ≤ 26.92 kg/m2 and stable or progressive disease as the best response had the shortest OS (11.2 months). CONCLUSIONS BMI and age may be predictors of PFS in lung SCC patients who receive GP treatment. BMI and best response to GP treatment predicts OS in such patients. Patients' clinical pathological characteristics may be used to predict the therapeutic efficacy of chemotherapy and survival.
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Affiliation(s)
- Jia Zhong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Qiwen Zheng
- Department of Epidemiology and Biostatistics, School of Public HealthPeking UniversityBeijingChina
| | - Emei Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Zhi Dong
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Jun Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Tongtong An
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Meina Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Minglei Zhuo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Yuyan Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Jianjie Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Shuhang Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Xue Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Hanxiao Chen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Bo Jia
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Jingjing Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
| | - Ziping Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology‐IPeking University Cancer Hospital and InstituteBeijingChina
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Kamel HFM, Al-Amodi HSAB. Exploitation of Gene Expression and Cancer Biomarkers in Paving the Path to Era of Personalized Medicine. GENOMICS PROTEOMICS & BIOINFORMATICS 2017; 15:220-235. [PMID: 28813639 PMCID: PMC5582794 DOI: 10.1016/j.gpb.2016.11.005] [Citation(s) in RCA: 72] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 10/29/2016] [Accepted: 11/11/2016] [Indexed: 02/06/2023]
Abstract
Cancer therapy agents have been used extensively as cytotoxic drugs against tissue or organ of a specific type of cancer. With the better understanding of molecular mechanisms underlying carcinogenesis and cellular events during cancer progression and metastasis, it is now possible to use targeted therapy for these molecular events. Targeted therapy is able to identify cancer patients with dissimilar genetic defects at cellular level for the same cancer type and consequently requires individualized approach for treatment. Cancer therapy begins to shift steadily from the traditional approach of “one regimen for all patients” to a more individualized approach, through which each patient will be treated specifically according to their specific genetic defects. Personalized medicine accordingly requires identification of indicators or markers that guide in the decision making of such therapy to the chosen patients for more effective therapy. Cancer biomarkers are frequently used in clinical practice for diagnosis and prognosis, as well as identification of responsive patients and prediction of treatment response of cancer patient. The rapid breakthrough and development of microarray and sequencing technologies is probably the main tool for paving the way toward “individualized biomarker-driven cancer therapy” or “personalized medicine”. In this review, we aim to provide an updated knowledge and overview of the current landscape of cancer biomarkers and their role in personalized medicine, emphasizing the impact of genomics on the implementation of new potential targeted therapies and development of novel cancer biomarkers in improving the outcome of cancer therapy.
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Affiliation(s)
- Hala Fawzy Mohamed Kamel
- Biochemistry Department, Faculty of Medicine, Umm AL-Qura University, Makhha 21955, Saudi Arabia; Medical Biochemistry Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.
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22
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Pilyugin M, Descloux P, André PA, Laszlo V, Dome B, Hegedus B, Sardy S, Janes S, Bianco A, Laurent GJ, Irminger-Finger I. BARD1 serum autoantibodies for the detection of lung cancer. PLoS One 2017; 12:e0182356. [PMID: 28786985 PMCID: PMC5546601 DOI: 10.1371/journal.pone.0182356] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 07/17/2017] [Indexed: 12/18/2022] Open
Abstract
PURPOSE Currently the screening for lung cancer for risk groups is based on Computed Tomography (CT) or low dose CT (LDCT); however, the lung cancer death rate has not decreased significantly with people undergoing LDCT. We aimed to develop a simple reliable blood test for early detection of all types of lung cancer based on the immunogenicity of aberrant forms of BARD1 that are specifically upregulated in lung cancer. METHODS ELISA assays were performed with a panel of BARD1 epitopes to detect serum levels of antibodies against BARD1 epitopes. We tested 194 blood samples from healthy donors and lung cancer patients with a panel of 40 BARD1 antigens. Using fitted Lasso logistic regression we determined the optimal combination of BARD1 antigens to be used in ELISA for discriminating lung cancer from healthy controls. Random selection of samples for training sets or validations sets was applied to validate the accuracy of our test. RESULTS Fitted Lasso logistic regression models predict high accuracy of the BARD1 autoimmune antibody test with an AUC = 0.96. Validation in independent samples provided and AUC = 0.86 and identical AUCs were obtained for combined stages 1-3 and late stage 4 lung cancers. The BARD1 antibody test is highly specific for lung cancer and not breast or ovarian cancer. CONCLUSION The BARD1 lung cancer test shows higher sensitivity and specificity than previously published blood tests for lung cancer detection and/or diagnosis or CT scans, and it could detect all types and all stages of lung cancer. This BARD1 lung cancer test could therefore be further developed as i) screening test for early detection of lung cancers in high-risk groups, and ii) diagnostic aid in complementing CT scan.
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Affiliation(s)
- Maxim Pilyugin
- Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, Medical Genetics and Laboratories, Geneva University Hospitals, Geneva, Switzerland
- * E-mail:
| | | | - Pierre-Alain André
- Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, Medical Genetics and Laboratories, Geneva University Hospitals, Geneva, Switzerland
| | - Viktoria Laszlo
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Balazs Dome
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
- National Koranyi Institute of Pulmonology, Budapest, Hungary
- Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary
| | - Balazs Hegedus
- Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
- Molecular Oncology Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hunagary
| | - Sylvain Sardy
- Departement of Mathematics, University of Geneva, Geneva, Switzerland
| | - Samuel Janes
- Lungs for Living Research Centre, UCL Respiratory, Rayne Institute, University College London, London, United Kingdom
| | - Andrea Bianco
- Dipartimento di Medicina e Scienze della Salute “V. Tiberio”, Università del Molise, Campobasso, Italy
| | - Geoffrey J. Laurent
- Institute for Respiratory Health, University of Western Australia and Harry Perkins Institute of Medical Research, Perth, Australia
| | - Irmgard Irminger-Finger
- Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, Medical Genetics and Laboratories, Geneva University Hospitals, Geneva, Switzerland
- Institute for Respiratory Health, University of Western Australia and Harry Perkins Institute of Medical Research, Perth, Australia
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El-Aarag SA, Mahmoud A, Hashem MH, Abd Elkader H, Hemeida AE, ElHefnawi M. In silico identification of potential key regulatory factors in smoking-induced lung cancer. BMC Med Genomics 2017; 10:40. [PMID: 28592245 PMCID: PMC5463402 DOI: 10.1186/s12920-017-0284-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 05/28/2017] [Indexed: 12/18/2022] Open
Abstract
Background Lung cancer is a leading cause of cancer-related death worldwide and is the most commonly diagnosed cancer. Like other cancers, it is a complex and highly heterogeneous disease involving multiple signaling pathways. Identifying potential therapeutic targets is critical for the development of effective treatment strategies. Methods We used a systems biology approach to identify potential key regulatory factors in smoking-induced lung cancer. We first identified genes that were differentially expressed between smokers with normal lungs and those with cancerous lungs, then integrated these differentially expressed genes (DEGs) with data from a protein-protein interaction database to build a network model with functional modules for pathway analysis. We also carried out a gene set enrichment analysis of DEG lists using the Kinase Enrichment Analysis (KEA), Protein-Protein Interaction (PPI) hubs, and KEGG (Kyoto Encyclopedia of Genes and Genomes) databases. Results Twelve transcription factors were identified as having potential significance in lung cancer (CREB1, NUCKS1, HOXB4, MYCN, MYC, PHF8, TRIM28, WT1, CUX1, CRX, GABP, and TCF3); three of these (CRX, GABP, and TCF) have not been previously implicated in lung carcinogenesis. In addition, 11 kinases were found to be potentially related to lung cancer (MAPK1, IGF1R, RPS6KA1, ATR, MAPK14, MAPK3, MAPK4, MAPK8, PRKCZ, and INSR, and PRKAA1). However, PRKAA1 is reported here for the first time. MEPCE, CDK1, PRKCA, COPS5, GSK3B, BRCA1, EP300, and PIN1 were identified as potential hubs in lung cancer-associated signaling. In addition, we found 18 pathways that were potentially related to lung carcinogenesis, of which 12 (mitogen-activated protein kinase, gonadotropin-releasing hormone, Toll-like receptor, ErbB, and insulin signaling; purine and ether lipid metabolism; adherens junctions; regulation of autophagy; snare interactions in vesicular transport; and cell cycle) have been previously identified. Conclusion Our systems-based approach identified potential key molecules in lung carcinogenesis and provides a basis for investigations of tumor development as well as novel drug targets for lung cancer treatment.
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Affiliation(s)
- Salem A El-Aarag
- Bioinformatics Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat City, Egypt
| | - Amal Mahmoud
- Bioinformatics Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat City, Egypt
| | - Medhat H Hashem
- Animal biotechnology Department, Genetic Engineering and Biotechnology Research Institute, (GEBRI), University of Sadat City, Sadat City, Egypt
| | - Hatem Abd Elkader
- Information Systems Department, Faculty of Computer and Information, Menoufia University, Al Minufiyah, Egypt
| | - Alaa E Hemeida
- Bioinformatics Department, Genetic Engineering and Biotechnology Research Institute (GEBRI), University of Sadat City, Sadat City, Egypt
| | - Mahmoud ElHefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Center, Cairo, Egypt. .,Center of Informatics, Nile university, Sheikh Zayed City, Giza, Egypt.
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Digennaro M, Sambiasi D, Tommasi S, Pilato B, Diotaiuti S, Kardhashi A, Trojano G, Tufaro A, Paradiso AV. Hereditary and non-hereditary branches of family eligible for BRCA test: cancers in other sites. Hered Cancer Clin Pract 2017; 15:7. [PMID: 28559958 PMCID: PMC5445420 DOI: 10.1186/s13053-017-0067-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 05/17/2017] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The analysis of relationships of BRCA alterations with cancer at sites other than breast/ovary may provide innovative information concerning BRCA pathogenic role and support additional clinical decisions. Aim of this study is to compare presence of cancers in other sites in members of hereditary (H) and not-hereditary (nH) branches of families of patients eligible to BRCA test. METHODS We retrospectively analyzed the incidence of cancer in other sites in members of 136 families eligible for hereditary breast/ovarian cancer genetic counseling at Centro Studi Tumori Eredo-familiari of our Institute; we compared the frequency of other cancer types in 1156 members of the H-branch with respect to 1062 members of nH-Branch. The families belonging to a proband case and with informative members in at least three generation entered the present study. RESULTS The frequency of other Cancers in members of H-branch was significantly higher than that in members of nH-branch (161 vs 75 cancers; p < 0.0001). In specific, members of H-branch had a significantly higher probability to have more lung cancer (38 vs 9;p < 0.0006), kidney cancer (23 vs 5;p < 0.0005), liver cancer (13 vs 3;p < 0.02) and larynx cancer (14 vs 4;p < 0.03). Interestingly, to belong to H-branch resulted significantly associated with a higher probability of lung cancer (OR 4.5; 2.15-9.38 95%C.I.), liver cancer (OR: 4.02; 1.14-14.15 95% C.I.) and larynx cancer (OR:3.4; 1.12-10.39 95%C.I.) independently from Gender and Age. CONCLUSIONS Members belonging to the H-branch of families of patients eligible to BRCA test have a higher risk of tumors in lung, larynx and liver. Clinicians should consider the increased risk for these cancers to activate prevention/early diagnosis practices in members of families with breast/ovarian familial cancer syndrome.
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Affiliation(s)
- M Digennaro
- Centro Studi Tumori Eredo-familiari. Istituto Tumori G Paolo II,IRCCS, 70124 Bari, Italy
| | - D Sambiasi
- Centro Studi Tumori Eredo-familiari. Istituto Tumori G Paolo II,IRCCS, 70124 Bari, Italy
| | - S Tommasi
- Laboratorio Genetica Molecolare; Istituto Tumori G Paolo II, IRCCS, 70124 Bari, Italy
| | - B Pilato
- Laboratorio Genetica Molecolare; Istituto Tumori G Paolo II, IRCCS, 70124 Bari, Italy
| | - S Diotaiuti
- UO Senologia Tumori. Istituto Tumori G Paolo II,IRCCS, 70124 Bari, Italy
| | - A Kardhashi
- UO Senologia Tumori. Istituto Tumori G Paolo II,IRCCS, 70124 Bari, Italy.,UO Ginecologia Oncologica, Istituto Tumori G Paolo II, IRCCS, 70124 Bari, Italy
| | - G Trojano
- ASST Fatebene Fratelli, Milan, Italy
| | - A Tufaro
- Biobanca Istituzionale, Istituto Tumori G Paolo II, IRCCS, 70124 Bari, Italy
| | - A V Paradiso
- Centro Studi Tumori Eredo-familiari. Istituto Tumori G Paolo II,IRCCS, 70124 Bari, Italy.,Centro Studi Tumori Eredo-Familiari, Istituto Tumori G Paolo II, IRCCS, Via O. Flacco, 65, 70124 Bari, Italy
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Fu Y, Browne JA, Killick K, Mulcahy G. Network Analysis of the Systemic Response to Fasciola hepatica Infection in Sheep Reveals Changes in Fibrosis, Apoptosis, Toll-Like Receptors 3/4, and B Cell Function. Front Immunol 2017; 8:485. [PMID: 28487699 PMCID: PMC5403899 DOI: 10.3389/fimmu.2017.00485] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 04/07/2017] [Indexed: 12/20/2022] Open
Abstract
The Trematode Fasciola hepatica is an important cause of disease in livestock and in man. Modulation of immunity is a critical strategy used by this parasite to facilitate its long-term survival in the host. Understanding the underlying mechanisms at a system level is important for the development of novel control strategies, such as vaccination, as well as for increasing general understanding of helminth-mediated immunoregulation and its consequences. Our previous RNA sequencing work identified a large number of differentially expressed genes (DEG) from ovine peripheral blood mononuclear cells (PBMCs) at acute and chronic stages of F. hepatica infection, and yielded important information on host–parasite interaction, with particular reference to the immune response. To extend our understanding of the immunoregulatory effects of this parasite, we employed InnateDB to further analyze the DEG dataset and identified 2,458 and 224 molecular interactions in the context of innate immunity from the acute and chronic stages of infection, respectively. Notably, 458 interactions at the acute stage of infection were manually curated from studies involving PBMC-related cell-types, which guaranteed confident hypothesis generation. NetworkAnalyst was subsequently used to construct and visualize molecular networks. Two complementary strategies (function-first and connection-first) were conducted to interpret the networks. The function-first approach highlighted subnetworks implicated in regulation of Toll-like receptor 3/4 signaling in both acute and chronic infections. The connection-first approach highlighted regulation of intrinsic apoptosis and B-cell receptor-signaling during acute and chronic infections, respectively. To the best of our knowledge, this study is the first system level analysis of the regulation of host innate immunity during F. hepatica infection. It provides insights into the profound changes induced by F. hepatica infection that not only favors parasite survival into chronic infection but also impedes the host’s immune response to other pathogens, and render vaccination against fasciolosis a difficult challenge. The information provided will be useful in the design of specific vaccine protocols to overcome parasite-mediated immunoregulation and in furthering general understanding of the interplay between helminth infection and host immune systems.
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Affiliation(s)
- Yan Fu
- UCD School of Veterinary Medicine, University College Dublin, Dublin, Ireland
| | - John A Browne
- UCD School of Agriculture and Food Science, University College Dublin, Dublin, Ireland
| | - Kate Killick
- UCD School of Agriculture and Food Science, University College Dublin, Dublin, Ireland
| | - Grace Mulcahy
- UCD School of Veterinary Medicine, University College Dublin, Dublin, Ireland.,UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
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Karachaliou N, Moreno MDLLG, Sosa AE, Santarpia M, Lazzari C, Capote AR, Massuti B, Rosell R. Using genetics to predict patient response to platinum-based chemotherapy. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2017. [DOI: 10.1080/23808993.2017.1298969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Niki Karachaliou
- Instituto of Oncology Rosell (IOR), University Hospital Sagrat Cor, Barcelona, Spain
| | | | - Aaron E. Sosa
- Instituto of Oncology Rosell (IOR), University Hospital Sagrat Cor, Barcelona, Spain
| | - Mariacarmela Santarpia
- Medical Oncology Unit, Department of Human Pathology ‘‘G. Barresi’’, University of Messina, Messina, Italy
| | - Chiara Lazzari
- Department of Oncology, Division of Experimental Medicine, IRCCS San Raffaele, Milan, Italy
| | | | - Bartomeu Massuti
- Medical Oncology Service, Hospital General de Alicante, Alicante, Spain
| | - Rafael Rosell
- Instituto of Oncology Rosell (IOR), Quirón-Dexeus University Institute, Barcelona, Spain
- Laboratory of Cancer Molecular Biology, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain
- Cancer Biology & Precision Medicine Laboratory, Catalan Institute of Oncology (ICO), Germans Trias i Pujol University Hospital, Badalona, Spain
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27
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Yin J, Zhao J, Hu W, Yang G, Yu H, Wang R, Wang L, Zhang G, Fu W, Dai L, Li W, Liao B, Zhang S. Disturbance of the let-7/LIN28 double-negative feedback loop is associated with radio- and chemo-resistance in non-small cell lung cancer. PLoS One 2017; 12:e0172787. [PMID: 28235063 PMCID: PMC5325287 DOI: 10.1371/journal.pone.0172787] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 01/18/2017] [Indexed: 12/19/2022] Open
Abstract
Radio- and chemo-resistance represent major obstacles in the therapy of non-small-cell lung cancer (NSCLC) and the underlying molecular mechanisms are not known. In the present study, during induction of radio- or chemo-resistance in NSCLC cells, dynamic analyses revealed that decreased expression of let-7 induced by irradiation or cisplatin resulted in increased expression of its target gene LIN28, and increased expression of LIN28 then contributed to further decreased expression of let-7 by inhibiting its maturation and biogenesis. Moreover, we showed that down-regulation of let-7 and up-regulation of LIN28 expression promoted resistance to irradiation or cisplatin by regulating the single-cell proliferative capability of NSCLC cells. Consequently, in NSCLC cells, let-7 and LIN28 can form a double-negative feedback loop through mutual inhibition, and disturbance of the let-7/LIN28 double-negative feedback loop induced by irradiation or chemotherapeutic drugs can result in radio- and chemo-resistance. In addition, low expression of let-7 and high expression of LIN28 in NSCLC patients was associated significantly with resistance to radiotherapy or chemotherapy. Therefore, our study demonstrated that disturbance of the let-7/LIN28 double-negative feedback loop is involved in the regulation of radio- and chemo-resistance, and that let-7 and LIN28 could be employed as predictive biomarkers of response to radiotherapy or chemotherapy in NSCLC patients.
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Affiliation(s)
- Jun Yin
- Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jian Zhao
- Department of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Weimin Hu
- Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Guangping Yang
- Department of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Hui Yu
- Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ruihao Wang
- Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Linjing Wang
- Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Guoqian Zhang
- Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Wenfan Fu
- Department of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Lu Dai
- Department of Chest Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Wanzhen Li
- Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Boyu Liao
- Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Shuxu Zhang
- Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, China
- * E-mail:
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Yang J, Chen J, Wei J, Liu X, Cho WC. Immune checkpoint blockade as a potential therapeutic target in non-small cell lung cancer. Expert Opin Biol Ther 2016; 16:1209-1223. [PMID: 27426430 DOI: 10.1080/14712598.2016.1214265] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 07/14/2016] [Indexed: 12/31/2022]
Abstract
INTRODUCTION The recent emergence of immune checkpoint blockade therapy and the progression of immunobiology in cancer have spurred an increasing interest in the immunotherapy for advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs), designed to directly target immune inhibitory molecules, have demonstrated efficacy in the treatment of patients with advanced NSCLC. AREAS COVERED In the present article, the authors summarize the mechanism, efficacy and safety of major ICIs for the treatment of advanced or metastatic NSCLC. Combinations of different ICIs or conventional therapy and/or targeted agents for NSCLC treatment in clinical trials are also updated. In addition, immune-related adverse events and the roles of inhibitory immune checkpoint molecules as potential biomarkers in the immune checkpoint blockade therapy for NSCLC are emphatically elucidated. EXPERT OPINION Immunotherapies targeting the immune checkpoint pathways have shown potential to generate durable responses and improve survival for NSCLC patients. Although the toxicity profile of this immunotherapy is manageable, immune-related adverse events and drug resistance may cause therapeutic failure. Therefore, a better understanding of the mechanisms underpinning its function and the potential side effects of ICIs, as well as the identification of predictive biomarkers for patient selection are essential.
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Affiliation(s)
- Jiali Yang
- a Center of Laboratory Medicine , General Hospital of Ningxia Medical University , Yinchuan , China
| | - Juan Chen
- b Department of Pulmonary and Critical Care Medicine , General Hospital of Ningxia Medical University , Yinchuan , China
| | - Jun Wei
- a Center of Laboratory Medicine , General Hospital of Ningxia Medical University , Yinchuan , China
- c Human Stem Cell Institute , General Hospital, Ningxia Medical University , Yinchuan , China
| | - Xiaoming Liu
- a Center of Laboratory Medicine , General Hospital of Ningxia Medical University , Yinchuan , China
- c Human Stem Cell Institute , General Hospital, Ningxia Medical University , Yinchuan , China
| | - William C Cho
- d Department of Clinical Oncology , Queen Elizabeth Hospital , Kowloon , Hong Kong
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Sun Y, Hou L, Yang Y, Xie H, Yang Y, Li Z, Zhao H, Gao W, Su B. Two-gene signature improves the discriminatory power of IASLC/ATS/ERS classification to predict the survival of patients with early-stage lung adenocarcinoma. Onco Targets Ther 2016; 9:4583-91. [PMID: 27524912 PMCID: PMC4966694 DOI: 10.2147/ott.s107272] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Background In this study, we investigated the contribution of a gene expression–based signature (composed of BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, SH3BGR) to survival prediction for early-stage lung adenocarcinoma categorized by the new International Association for the Study of Lung Cancer (IASLC)/the American Thoracic Society (ATS)/the European Respiratory Society (ERS) classification. We also aimed to verify whether gene signature improves the risk discrimination of IASLC/ATS/ERS classification in early-stage lung adenocarcinoma. Patients and methods Total RNA was extracted from 93 patients with pathologically confirmed TNM stage Ia and Ib lung adenocarcinoma. The mRNA expression levels of ten genes in the signature (BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, IL11, LCK, RND3, and SH3BGR) were detected using real-time polymerase chain reaction. Each patient was categorized according to the new IASLC/ATS/ERS classification by accessing hematoxylin–eosin-stained slides. The corresponding Kaplan–Meier survival analysis by the log-rank statistic, multivariate Cox proportional hazards modeling, and c-index calculation were conducted using the programming language R (Version 2.15.1) with the “risksetROC” package. Results The multivariate analysis demonstrated that the risk factor of the ten-gene expression signature can significantly improve the discriminatory value of TNM staging in survival prediction, but not the value of the IASLC/ATS/ERS classification. Further analysis suggested that only BRCA1 and ERBB3 in the signature were independent risk factors after adjusting for the IASLC/ATS/ERS classification by Cox regression. A new algorithm of the two-gene expression signature containing BRCA1 and ERBB3 was generated. Adding the two-gene signature into the IASLC/ATS/ERS classification model further improved the discriminatory c-statistic from 0.728 to 0.756. Conclusion The two-gene signature composed of BRCA1 and ERBB3 was an independent risk factor of the IASLC/ATS/ERS classification, which can be used to improve the discriminatory power of prognosis prediction of the IASLC/ATS/ERS classification in early-stage lung adenocarcinoma. The two-gene signature combination with the IASLC/ATS/ERS classification might contribute to better patient stratification for adjuvant chemoradiotherapy or targeted therapy after the surgery.
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Affiliation(s)
- Yifeng Sun
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University
| | - Likun Hou
- Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai
| | - Yu Yang
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University
| | - Huikang Xie
- Department of Pathology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai
| | - Yang Yang
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University
| | - Zhigang Li
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University
| | - Heng Zhao
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiaotong University
| | - Wen Gao
- Department of Thoracic Surgery, Shanghai Huadong Hospital, Fudan University School of Medicine, Shanghai
| | - Bo Su
- Central Lab, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China
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Can the response to a platinum-based therapy be predicted by the DNA repair status in non-small cell lung cancer? Cancer Treat Rev 2016; 48:8-19. [DOI: 10.1016/j.ctrv.2016.05.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 04/04/2016] [Accepted: 05/12/2016] [Indexed: 12/17/2022]
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Song W, Ma H. The expression of ERCC1 and BRCA1 predicts prognosis of platinum-based chemotherapy in urothelial cancer. Onco Targets Ther 2016; 9:3465-71. [PMID: 27366083 PMCID: PMC4913982 DOI: 10.2147/ott.s101319] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Objective To investigate the expression and clinical significance of ERCC1 and BRCA1 genes in urothelial cancer patients. Methods Forty-two urothelial cancer patients who did not receive platinum-based chemotherapy during January 2009 to May 2013 were enrolled. The expression levels of ERCC1 and BRCA1 were determined by immunohistochemistry and the median survival time (MST) for these patients was calculated. Results ERCC1-positive patients who received oxaliplatin-based chemotherapy had a shorter MST than ERCC1-negative patients (P<0.05), whereas there is no difference of MST between BRCA1-positive and -negative patients. Furthermore, MST in ERCC1 and BRCA1 double-positive patients was shorter than ERCC1 and BRCA1 double-negative patients (P<0.05). The positive expression of ERCC1 had a significant positive correlation with BRCA1 (r=0.313, P=0.044). Conclusion The expression level of ERCC1 may be used as a prognostic marker for urothelial cancer patients who received postoperative adjuvant chemotherapy.
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Affiliation(s)
- Wenhui Song
- Department of Urology, Tianjin First Center Hospital, Tianjin, People's Republic of China
| | - Hongshun Ma
- Department of Urology, Tianjin First Center Hospital, Tianjin, People's Republic of China
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Wallerek S, Sørensen JB. Biomarkers for efficacy of adjuvant chemotherapy following complete resection in NSCLC stages I-IIIA. Eur Respir Rev 2016; 24:340-55. [PMID: 26028645 PMCID: PMC9487808 DOI: 10.1183/16000617.00005814] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Biomarkers may be useful when deciding which nonsmall cell lung cancer (NSCLC) patients may benefit from adjuvant chemotherapy following complete resection and which chemotherapeutic agents may be used preferably in individual patients in order to maximise survival. A literature search covering the period from 2003 to May, 2014 was conducted using PubMed and the following search terms: “non-small cell lung cancer”, “NSCLC”, “adjuvant chemotherapy”, “randomized”, “randomised”, “biomarkers”, “prognostic”, “predictive”. This review focuses on current knowledge of biomarkers for prognosis or efficacy of adjuvant treatment following complete resection in stage I–IIIA NSCLC patients. This review includes results on 18 different biomarkers and five gene profiles. A statistically significant prognostic impact was reported for: iNTR, TUBB3, RRM1, ERCC1, BRCA1, p53, MRP2, MSH2, TS, mucin, BAG-1, pERK1/2, pAkt-1, microRNA, TopIIA, 15-gene profile, 92-gene profile, 31-gene profile and 14-gene profile. A statistically significant predictive impact was reported for: ERCC1, p53, MSH2, p27, TUBB3, PARP1, ATM, 37-gene profile, 31-gene profile, 15-gene profile and 92-gene profile. Uncertainties regarding the optimal analysis method and cut-off levels for the individual markers may blur the prognostic or predictive signals. None of the possible predictive markers have been validated in prospective trials. Thus, there are no biomarkers ready to use in an adjuvant setting in NSCLC. Further investigation and validation is required to explore biomarkers in completely resected NSCLC stage I–IIIAhttp://ow.ly/M0leE
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Affiliation(s)
- Sandra Wallerek
- Dept of Oncology, Finsen Centre, Copenhagen University Hospital, Copenhagen, Denmark
| | - Jens Benn Sørensen
- Dept of Oncology, Finsen Centre, Copenhagen University Hospital, Copenhagen, Denmark
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Biomarkers in early-stage non-small-cell lung cancer: current concepts and future directions. J Thorac Oncol 2015; 9:1609-17. [PMID: 25185530 DOI: 10.1097/jto.0000000000000302] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Advances in molecular biology and bioinformatics have resulted in the identification of a number of potential biomarkers that could be relevant in the management of patients with non-small-cell lung cancer (NSCLC). Although there is an increasing amount of literature related to these biomarkers, major issues need to be resolved including validity and reproducibility of results. Additionally, in order to interpret the existing literature accurately, a clear distinction must be made between the prognostic and predictive value of biomarkers. The practical applicability of biomarker discovery for patients with lung cancer includes the identification of patients with early-stage NSCLC who are most likely to benefit from adjuvant therapy. Information gleaned from biomarkers has the potential to help in evaluating the role of targeted therapies including immunotherapy in the neoadjuvant and adjuvant setting. The role of gene signatures and the use of newer platforms such as RNA, methylation, and protein signatures is being explored in patients with early-stage NSCLC. This review focuses on the applications of biomarker discovery in patients with early-stage NSCLC.
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Expression of Ribonucleotide Reductase Subunit-2 and Thymidylate Synthase Correlates with Poor Prognosis in Patients with Resected Stages I-III Non-Small Cell Lung Cancer. DISEASE MARKERS 2015; 2015:302649. [PMID: 26663950 PMCID: PMC4664813 DOI: 10.1155/2015/302649] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Revised: 10/05/2015] [Accepted: 10/07/2015] [Indexed: 12/12/2022]
Abstract
Biomarkers can help to identify patients with early-stages or locally advanced non-small cell lung cancer (NSCLC) who have high risk of relapse and poor prognosis. To correlate the expression of seven biomarkers involved in DNA synthesis and repair and in cell division with clinical outcome, we consecutively collected 82 tumour tissues from radically resected NSCLC patients. The following biomarkers were investigated using IHC and qRT-PCR: excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2), subunit p53R2, thymidylate synthase (TS), and class III beta-tubulin (TUBB3). Gene expression levels were also validated in an available NSCLC microarray dataset. Multivariate analysis identified the protein overexpression of RRM2 and TS as independent prognostic factors of shorter overall survival (OS). Kaplan-Meier analysis showed a trend in shorter OS for patients with RRM2, TS, and ERCC1, BRCA1 overexpressed tumours. For all of the biomarkers except TUBB3, the OS trends relative to the gene expression levels were in agreement with those relative to the protein expression levels. The NSCLC microarray dataset showed RRM2 and TS as biomarkers significantly associated with OS. This study suggests that high expression levels of RRM2 and TS might be negative prognostic factors for resected NSCLC patients.
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Prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 in early stage of non-small cell lung cancer. Clin Transl Oncol 2015; 18:798-804. [PMID: 26542178 DOI: 10.1007/s12094-015-1440-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 10/26/2015] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Nowadays, 40 % of early-stage NSCLC patients relapse in the 2 years following resection, suggesting a mis-staging in this group of patients who are not receiving adjuvant chemotherapy. Although different biomarkers, such as ERCC1, RRM1 and BRCA1 have been found to present prognostic value in advanced NSCLC patients, in early-stage NSCLC patients its relevance remains unclear. Moreover, SETDB1 has been recently proposed as a bona fide oncogene in lung tumourigenesis and related with metastasis. The aim of the present study was to analyze the prognostic value of ERCC1, RRM1, BRCA1 and SETDB1 expression levels in NSCLC patients at stage I. PATIENTS AND METHODS ERCC1, RRM1, BRCA1 and SETDB1 expression at mRNA level was analyzed by real-time quantitative RT-PCR in fresh-frozen tumor and normal adjacent lung tissue samples from 64 stage I NSCLC patients. Later, significant association between gene expression levels, clinicopathological characteristics and patient's disease-free survival was assessed. RESULTS We did not find any statistically significant correlation between gene expression and gender, age, histological type or smoking status. Univariate followed by multivariate Cox analysis showed that higher levels of BRCA1 and SETDB1 expression were significantly associated with shorter disease-free survival in stage I NSCLC patients. CONCLUSION Our study finds that ERCC1 and RRM1 are not independent prognostic factors of recurrence in stage I NSCLC patients. By contrast, BRCA1 and SETDB1 stand out as the most significant prognostic markers in this group of patients, appearing as promising tools to predict tumor recurrence in early-stage NSCLC patients.
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Zhao J, Fu W, Liao H, Dai L, Jiang Z, Pan Y, Huang H, Mo Y, Li S, Yang G, Yin J. The regulatory and predictive functions of miR-17 and miR-92 families on cisplatin resistance of non-small cell lung cancer. BMC Cancer 2015; 15:731. [PMID: 26482648 PMCID: PMC4617718 DOI: 10.1186/s12885-015-1713-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Accepted: 10/08/2015] [Indexed: 12/20/2022] Open
Abstract
Background Chemotherapy is an important therapeutic approach for non-small cell lung cancer (NSCLC). However, a successful long-term treatment can be prevented by the occurring of chemotherapy resistance frequently, and the molecular mechanisms of chemotherapy resistance in NSCLC remain unclear. In this study, abnormal expressions of miR-17 and miR-92 families are observed in cisplatin-resistant cells, suggesting that miR-17 and miR-92 families are involved in the regulation of cisplatin resistance in NSCLC. Methods miRNA microarray shows that miR-17 and miR-92 families are all down-regulated in cisplatin-resistant A549/DDP cells compared with cisplatin-sensitive A549 cells. The aim of this study is to investigate the regulatory functions of miR-17 and miR-92 families on the formation of cisplatin resistance and the predictive functions of them as biomarkers of platinum-based chemotherapy resistance in NSCLC. Results The low expressions of miR-17 and miR-92 families can maintain cisplatin resistance through the regulation of CDKN1A and RAD21. As a result of high expressions of CDKN1A and RAD21, the inhibition of DNA synthesis and the repair of DNA damage are achieved and these may be two major contributing factors to cisplatin resistance. Moreover, we demonstrate that the expressions of miR-17 and miR-92 families in NSCLC tissues are significantly associated with platinum-based chemotherapy response. Conclusion Our study indicates that miR-17 and miR-92 families play important roles in cisplatin resistance and can be used as potential biomarkers for better predicting the clinical response to platinum-based chemotherapy in NSCLC. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1713-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jian Zhao
- Department of Chest Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Wenfan Fu
- Department of Chest Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Hongying Liao
- Department of Chest Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Lu Dai
- Department of Chest Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Zeyong Jiang
- Department of Chest Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Youguang Pan
- Department of Chest Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Haoda Huang
- Department of Chest Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Yijun Mo
- Department of Chest Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Siwen Li
- Department of Chest Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Guangping Yang
- Department of Chest Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Jun Yin
- Department of Chest Surgery, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong, China.
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Feng W, Deng Y, Wu J, Zhang H, Liang J, Xian H, Yang S. Overexpression of BRCA1 attenuates the sensitivity of PC9 cells to gefitinib. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:12869-12876. [PMID: 26722478 PMCID: PMC4680423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 10/25/2015] [Indexed: 06/05/2023]
Abstract
Gefitinib is an orally active antitumor agent which inhibits uncontrolled cell proliferation by interrupting epidermal growth factor receptor (EGFR) signaling pathways. Various in vitro and in vivo studies have revealed that the upregulated expression of breast cancer susceptibility gene 1 (BRCA1) is associated with chemoresistance and reduced survival following chemotherapies. In this study, a gefitinib-highly-sensitive cell line, PC-9, was used to investigate the effect of BRCA1 expression on the sensitivity of PC-9 cells to gefitinib. PC-9 cells were stably transfected with BRCA-1 (HA-tagged). Transfected and untransfected PC-9 cells were treated with gefitinib, phosphorylated γH2AX was examined by western blot to determine the DNA damages. Following the treatment of gefitinib, the inhibition of proliferation of the PC-9 cells, PC-9-pcDNA3.1 cells, and BRCA1-transfected PC-9 cells were determined. Also, a comet assay was performed to determine the DNA damage caused by gefitinib. The treatment of gefitinib for 6 hr, 12 h, and 24 hr significantly increased the cellular expression of phosphorylated γH2AX. With the treatment of gefitinib, the inhibition of proliferation of BRCA-1 overexpressed PC-9 cells was significantly lower than that of the non-transfected PC-9 cells, indicating the overexpression of BRCA1 plays a role in attenuating the sensitivity of PC-9 cells to gefitinib. The comet assay revealed that BRCA1 transfected cells showed a shorter comet tail, indicating the overexpression of BRCA1 attenuated the DNA damages caused by gefitinib. The overexpression of BRCA1 reduced the DNA damages, and enhanced DNA repair mechanisms. Also, gefitinib-mediated inhibition of cell proliferation is attenuated by the expression of BRCA1.
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Affiliation(s)
- Weineng Feng
- Department of Head and Neck/Thoracic Medical Oncology, The First People’s Hospital of FoshanFoshan 528000, Guangdong, P. R. China
| | - Yanming Deng
- Department of Head and Neck/Thoracic Medical Oncology, The First People’s Hospital of FoshanFoshan 528000, Guangdong, P. R. China
| | - Jing Wu
- Institute of Oncology, The First People’s Hospital of FoshanFoshan 528000, Guangdong, P. R. China
| | - Hua Zhang
- Department of Head and Neck/Thoracic Medical Oncology, The First People’s Hospital of FoshanFoshan 528000, Guangdong, P. R. China
| | - Jianmao Liang
- Department of Head and Neck/Thoracic Medical Oncology, The First People’s Hospital of FoshanFoshan 528000, Guangdong, P. R. China
| | - Haibing Xian
- Department of Head and Neck/Thoracic Medical Oncology, The First People’s Hospital of FoshanFoshan 528000, Guangdong, P. R. China
| | - Shuang Yang
- Department of Head and Neck/Thoracic Medical Oncology, The First People’s Hospital of FoshanFoshan 528000, Guangdong, P. R. China
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Zhao XD, He YY, Gao J, Zhao C, Zhang LL, Tian JY, Chen HL. High expression of Bcl-2 protein predicts favorable outcome in non-small cell lung cancer: evidence from a systematic review and meta-analysis. Asian Pac J Cancer Prev 2015; 15:8861-9. [PMID: 25374220 DOI: 10.7314/apjcp.2014.15.20.8861] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The prognostic value of Bcl-2 protein expression in non-small cell lung cancer (NSCLC) is under debate. We therefore systematically reviewed the evidence for Bcl-2 protein effects on NSCLC survival to elucidate this issue. MATERIALS AND METHODS An electronic search in Pubmed and Embase complemented by manual searches in article references were conducted to identify eligible studies to evaluate the association between Bcl-2 protein expression and overall survival (OS) as well as disease free survival (DFS) of NSCLC patients. Combined hazard ratios (HRs) with corresponding 95% confidence intervals (95%CIs) were pooled using the random-effects model. RESULTS A total of 50 trials (including 52 cohorts) encompassing 7,765 patients were pooled in the meta-analysis regarding Bcl-2 expression and OS of NSCLC patients. High expression of Bcl-2 protein had a favorable impact (HR=0.76, 95%CI=0.67-0.86). In the group of Bcl-2 expression and DFS, 11 studies including 2,634 patients were included. The synthesized result indicated high expression of Bcl-2 protein might predict good DFS (HR=0.85, 95%CI=0.75-0.95). CONCLUSIONS Our present meta-analysis demonstrated favorable prognostic values of Bcl-2 expression in patients with NSCLC. Further prospective trails are welcomed to validate the utility of assessing Bcl-2 in NSCLC patient management.
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Affiliation(s)
- Xian-Da Zhao
- Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan, China E-mail :
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Koriyama H, Ishii G, Yoh K, Neri S, Morise M, Umemura S, Matsumoto S, Niho S, Ohmatsu H, Tsuboi M, Goto K, Ochiai A. Presence of podoplanin-positive cancer-associated fibroblasts in surgically resected primary lung adenocarcinoma predicts a shorter progression-free survival period in patients with recurrences who received platinum-based chemotherapy. J Cancer Res Clin Oncol 2015; 141:1163-70. [PMID: 25446816 DOI: 10.1007/s00432-014-1891-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 11/25/2014] [Indexed: 01/05/2023]
Abstract
PURPOSE The influence of microenvironmental factors on the effectiveness of chemotherapy is being increasingly recognized. The purpose of this study was to investigate the relationships between cancer cell and stromal cell phenotypes in primary tumors and the progression-free survival (PFS) of recurrent lung cancer patients who received platinum-based chemotherapy. METHODS We retrospectively analyzed 87 postoperative recurrent lung adenocarcinoma patients treated with platinum-based chemotherapy. The expressions of drug resistance-related proteins including BCRP, ezrin, and ALDH1 in cancer cells, the number of CD204-positive tumor-associated macrophages (TAMs), and the presence of podoplanin-positive cancer-associated fibroblasts (CAFs) in the primary tumor were examined. The relationships between the immunohistochemical staining results of primary tumors and the PFS after receiving chemotherapy were also analyzed. RESULTS Among the clinicopathological factors of primary tumors, only an advanced pathological stage was significantly associated with a shorter PFS. As for immunohistochemical staining, no significant relationships were found between the PFS and the expression of BCRP, ezrin, or ALDH1. Although the number of CD204-positive TAMs was not associated with the PFS, the presence of podoplanin-positive CAFs was significantly associated with a shorter PFS (median PFS: 5.1 vs. 7.8 months, P = 0.028). A multivariate analysis revealed a tendency of podoplanin-positive CAFs to be correlated with a shorter PFS (P = 0.087). CONCLUSIONS The presence of podoplanin-positive CAFs in the primary tumor could be a predictor of a shorter PFS in recurrent lung adenocarcinoma patients who received chemotherapy. These findings suggest that stromal-cell-derived factors should be incorporated into predictions of the effectiveness of chemotherapy.
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Affiliation(s)
- Haruki Koriyama
- Pathology Division, Department of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
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刘 博, 丁 凤, 杨 双. [Progress of Postoperative Adjuvant Chemotherapy in Stage I Non-small Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2015; 18:374-80. [PMID: 26104895 PMCID: PMC5999912 DOI: 10.3779/j.issn.1009-3419.2015.06.08] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 04/28/2015] [Indexed: 11/05/2022]
Abstract
The morbidity and mortality of lung cancer rank the first place among all the malignant tumor. According to the histopathological characteristics, lung cancer is divided into non-small cell lung cancer (NSCLC) and small cell lung cancer. Only 20% patients diagnosed with NSCLC have the chance for surgery while their 5-yr overall survival is about 30%-60%. The therapeutic outcome of surgery alone is not satisfying. Adjuvant chemotherapy after surgical resection in stage II-IIIa lung cancer showed efficacy in many randomized clinical trials, but its role in stage I disease remains controversial. The choice of appropriate chemotherapy candidates, the selection of chemotherapy regimens and the research progress on biomarker are mainly discussed in this review.
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Affiliation(s)
- 博 刘
- />400016 重庆，重庆医科大学附属第一医院胸心外科Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - 凤霞 丁
- />400016 重庆，重庆医科大学附属第一医院胸心外科Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - 双强 杨
- />400016 重庆，重庆医科大学附属第一医院胸心外科Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
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Shi Q, Liu X, Zeng T, Wang W, Chen L. Detecting disease genes of non-small lung cancer based on consistently differential interactions. Cancer Metastasis Rev 2015; 34:195-208. [DOI: 10.1007/s10555-015-9561-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Carnio S, Novello S, Papotti M, Loiacono M, Scagliotti GV. Prognostic and predictive biomarkers in early stage non-small cell lung cancer: tumor based approaches including gene signatures. Transl Lung Cancer Res 2015; 2:372-81. [PMID: 25806256 DOI: 10.3978/j.issn.2218-6751.2013.10.05] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2013] [Accepted: 10/10/2013] [Indexed: 12/26/2022]
Abstract
In early stage non-small cell lung cancer (NSCLC) large randomized trials have demonstrated that in patients with radically resected disease adjuvant chemotherapy improves 5-year survival rates. However, a customization of systemic treatment is needed to avoid treatments in patients cured by surgery alone or to justify the use of adjuvant chemotherapy in high risk patients, including those in stage IA. Recently, the possibility of identifying prognostic and predictive factors related to the genetic signatures of the tumor that could affect adjuvant and neo-adjuvant treatment choices for resectable non-small cell lung cancer (NSCLC) has been of interest. This review summarizes the current status and future opportunities for clinical application of genotyping and genomic tests in early NSCLC.
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Affiliation(s)
- Simona Carnio
- University of Torino, Department of Oncology, Torino, Italy
| | - Silvia Novello
- University of Torino, Department of Oncology, Torino, Italy
| | - Mauro Papotti
- University of Torino, Department of Oncology, Torino, Italy
| | - Marco Loiacono
- University of Torino, Department of Oncology, Torino, Italy
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Massuti B, Sanchez JM, Hernando-Trancho F, Karachaliou N, Rosell R. Are we ready to use biomarkers for staging, prognosis and treatment selection in early-stage non-small-cell lung cancer? Transl Lung Cancer Res 2015; 2:208-21. [PMID: 25806234 DOI: 10.3978/j.issn.2218-6751.2013.03.06] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Accepted: 03/11/2013] [Indexed: 01/16/2023]
Abstract
Lung cancer accounts for the majority of cancer-related deaths worldwide. At present, platinum-based therapy represents the standard of care in fit stage II and IIIA non-small cell lung cancer (NSCLC) patients following surgical resection. In advanced disease, personalized chemotherapy and targeted biologic therapy based on histological and molecular tumor profiling have already shown promise in terms of optimizing treatment efficacy. While disease stage is associated with outcome and is commonly used to determine adjuvant treatment eligibility, it is known that a subset of patients with early stage disease experience shorter survival than others with the same clinicopathological characteristics. Improved methods for identifying these individuals, at or near the time of initial diagnosis, may inform the decision to pursue adjuvant therapy options. Among the numerous candidate molecular biomarkers, only few gene-expression profiling signatures provide clinically relevant information, while real-time quantitative polymerase-chain reaction (RT-qPCR) strategy involving relatively small numbers of genes offers a practical alternative with high cross-platform performance. mRNA and/or protein expression levels of excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase M subunit 1 (RRM1) and breast cancer susceptibility gene 1 (BRCA1) are among the most promising potential biomarkers for early disease and their clinical utility is currently being evaluated in randomized phase II and III clinical trials. This review describes the most promising clinicopathological and molecular biomarkers with predictive and prognostic significance in lung cancer that have been identified through advanced research and which could influence adjuvant and neoadjuvant chemotherapy decisions for operable NSCLC in routine clinical practice.
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Affiliation(s)
| | | | | | - Niki Karachaliou
- Breakthrough Cancer Research Unit, Pangaea Biotech S.L, Barcelona, Spain
| | - Rafael Rosell
- Breakthrough Cancer Research Unit, Pangaea Biotech S.L, Barcelona, Spain ; ; Catalan Institute of Oncology, Badalona, Spain
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Bonanno L. Predictive models for customizing chemotherapy in advanced non-small cell lung cancer (NSCLC). Transl Lung Cancer Res 2015; 2:160-71. [PMID: 25806229 DOI: 10.3978/j.issn.2218-6751.2013.03.07] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Accepted: 03/12/2013] [Indexed: 01/06/2023]
Abstract
The backbone of first-line treatment for Epidermal Growth Factor (EGFR) wild-type (wt) advanced Non-small cell lung cancer (NSCLC) patients is the use of a platinum-based chemotherapy combination. The treatment is characterized by great inter-individual variability in outcome. Molecular predictive markers are extremely needed in order to identify patients most likely to benefit from platinum-based treatment and resistant ones, thus optimizing chemotherapy approach in NSCLC. Several components of DNA repair response (DRR) have been investigated as potential predictive markers. Among them, high levels of expression of ERCC1, both at protein and mRNA levels, have been associated with resistance to cisplatin in NSCLC. In addition, low levels of expression of RRM1, a target for gemcitabine, have been associated with improved OS in advanced NSCLC patients treated with cisplatin and gemcitabine. Preclinical data and retrospective analyses showed that BRCA1 is able to induce resistance to cisplatin and sensitivity to antimicrotubule agents. In addition, the mRNA levels of expression of RAP80, encoding for a protein cooperating with BRCA1 in homologous recombination (HR), have demonstrated to further sub-classify low BRCA1 NSCLC tumors, improving the predictive model. On the basis of biological knowledge on DNA repair pathway and recent controversial results from clinical validation of potential molecular markers, integrated analysis of multiple DNA repair components could improve predictive information and pave the way to a new approach to customized chemotherapy clinical trials.
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Affiliation(s)
- Laura Bonanno
- Medical Oncology 2, Istituto Oncologico Veneto I.R.C.C.S., Padova, Italia
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Abstract
The Hippo pathway regulates cell proliferation and apoptosis through the Yes-associated protein (YAP) transcriptional activator. YAP has a well-described role in promoting cell proliferation and survival, but the precise mechanisms and transcriptional targets that underlie these properties are still unclear and likely context-dependent. We found, using siRNA-mediated knockdown, that YAP is required for proliferation in endothelial cells but not HeLa cells. Specifically, YAP is required for S-phase entry and its absence causes cells to accumulate in G1. Microarray analysis suggests that YAP mediates this effect by regulating the transcription of genes involved in the assembly and/or firing of replication origins and homologous recombination of DNA. These findings thus provide insight into the molecular mechanisms by which YAP regulates cell cycle progression.
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Xie KJ, He HE, Sun AJ, Liu XB, Sun LP, Dong XJ. Expression of ERCC1, MSH2 and PARP1 in non-small cell lung cancer and prognostic value in patients treated with platinum-based chemotherapy. Asian Pac J Cancer Prev 2015; 15:2591-6. [PMID: 24761869 DOI: 10.7314/apjcp.2014.15.6.2591] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
PURPOSE To evaluate the prognostic value of the expression of excision repair cross-complementation group l (ERCC1), MutS protein homolog 2 (MSH2) and poly ADP-ribose polymerase 1 (PARP1) in non-small-cell lung cancer patients receiving platinum-based postoperative adjuvant chemotherapy. METHODS Immunohistochemistry was applied to detect the expression of ERCC1, MSH2 and PARP1 in 111 cases of non-small cell lung cancer paraffin embedded surgical specimens. Through og-rank survival analysis, we evaluated the prognostic value of the ERCC1, MSH2, PARP1 and the related clinicopathological factors. COX regression analysis was used to determine whether ERCC1, MSH2 and PARP1 were independent prognostic factors. RESULTS In the enrolled 111 non-small cell lung cancer patients, the positive expression rate of ERCC1, MSH2 and RARP1 was 33.3%, 36.9% and 55.9%, respectively. ERCC1 (P<0.001) and PARP1 (P=0.033) were found to be correlated with the survival time while there was no correlation for MSH2 (P=0.298). Patients with both ERCC1 and PARP1 negative cancer had significantly longer survival time than those with ERCC1 (P=0.042) or PARP1 (P=0.027) positive alone. Similalry, the survival time of patients with both ERCC1 and PARP1 positive cancer was shorter than those with ERCC1 (P=0.048) or PARP1 (P=0.01) positive alone. CONCLUSION Patients with ERCC1 or PARP1 negative non-small cell lung cancer appear to benefit from platinum-based postoperative adjuvant chemotherapy.
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Affiliation(s)
- Ke-Jie Xie
- Clinical Examination Center, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China E-mail :
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Kawai H. Estrogen receptors as the novel therapeutic biomarker in non-small cell lung cancer. World J Clin Oncol 2014; 5:1020-1027. [PMID: 25493237 PMCID: PMC4259928 DOI: 10.5306/wjco.v5.i5.1020] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2014] [Revised: 06/23/2014] [Accepted: 09/10/2014] [Indexed: 02/06/2023] Open
Abstract
Although a wide range of studies have addressed the relationship between estrogen receptor (ER) expression and prognosis in non-small cell lung cancer (NSCLC), that relationship remains controversial. This is in large part because there is no consensus on the rate of ER expression in NSCLC or on the intracellular distribution of ER expression. This suggests that establishing the relationship between ER expression and prognosis will require standardization of the antibodies used as well as the definition of a positive response. For example, it is supposed from previous studies that ERs in the cytoplasm and nucleus have different relationships to prognosis than ERs in the cytoplasm. Moreover, ER signaling in NSCLC is known to be affected by aromatase, progesterone receptor and epidermal growth factor receptor mutation. However, there has been little functional analysis these mutants and subtypes. This review will focus on what is known about the role of ERs in NSCLC and whether ER can be a useful prognostic marker or therapeutic target in NSCLC.
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Zer A, Leighl N. Promising Targets and Current Clinical Trials in Metastatic Non-Squamous NSCLC. Front Oncol 2014; 4:329. [PMID: 25505733 PMCID: PMC4243502 DOI: 10.3389/fonc.2014.00329] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 10/31/2014] [Indexed: 11/24/2022] Open
Abstract
Lung adenocarcinoma is the most common subtype of lung cancer today. With the discovery of epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and effective targeted therapy, personalized medicine has become a reality for patients with lung adenocarcinoma. Here, we review potential additional targets and novel therapies of interest in lung adenocarcinoma including targets within the cell surface (receptor tyrosine kinases EGFR, human epidermal growth factor receptor 2, RET, ROS1, mesenchymal-epidermal transition, TRK), targets in intracellular signal transduction (ALK, RAS-RAF-MEK, PI3K-AKT-PTEN, WNT), nuclear targets such as poly-ADP ribose polymerase, heat shock protein 90, and histone deacetylase, and selected pathways in the tumor environment. With the evolving ability to identify specific molecular aberrations in patient tumors in routine practice, our ability to further personalize therapy in lung adenocarcinoma is rapidly expanding.
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Affiliation(s)
- Alona Zer
- Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Natasha Leighl
- Division of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
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Byron E, Pinder-Schenck M. Systemic and targeted therapies for early-stage lung cancer. Cancer Control 2014; 21:21-31. [PMID: 24357738 DOI: 10.1177/107327481402100104] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Even with aggressive surgical treatment, relapse rates remain high for patients with resectable non-small-cell lung cancer (NSCLC). In an effort to improve survival in these patients, numerous clinical trials have evaluated neoadjuvant and adjuvant chemotherapy. METHODS The authors reviewed the results of the prospective randomized clinical trials that have established adjuvant chemotherapy as the standard of care for patients with surgically resected NSCLC. In addition, the authors summarize data on predictive and prognostic markers for patients with early-stage NSCLC and discuss novel therapies and clinical trials currently underway in early-stage NSCLC. RESULTS Three large randomized clinical trials and two meta-analyses have demonstrated a survival benefit for adjuvant cisplatin-based chemotherapy compared with surgery alone in patients with early-stage NSCLC. As a result, adjuvant cisplatin-based chemotherapy is recommended as the standard of care in these patients. Numerous promising biomarkers and agents have been developed in the metastatic setting and are currently being evaluated in the adjuvant setting. CONCLUSIONS While adjuvant chemotherapy has improved survival for patients with early-stage NSCLC, the prognosis for early-stage lung cancer remains poor. Incorporation of molecular markers and targeted therapies into the management of patients with advanced NSCLC has improved outcomes. Development of these strategies in the adjuvant setting offers the potential to increase cure rates in patients with early-stage NSCLC.
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Affiliation(s)
- Elizabeth Byron
- Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.
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Ruiz R, Hunis B, Raez LE. Immunotherapeutic Agents in Non-small-cell Lung Cancer Finally Coming to the Front Lines. Curr Oncol Rep 2014; 16:400. [DOI: 10.1007/s11912-014-0400-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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